CA2484691A1 - A nutriceutical composition for the correction of impaired endothelium-dependent arterial vasomotor response - Google Patents
A nutriceutical composition for the correction of impaired endothelium-dependent arterial vasomotor response Download PDFInfo
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- CA2484691A1 CA2484691A1 CA002484691A CA2484691A CA2484691A1 CA 2484691 A1 CA2484691 A1 CA 2484691A1 CA 002484691 A CA002484691 A CA 002484691A CA 2484691 A CA2484691 A CA 2484691A CA 2484691 A1 CA2484691 A1 CA 2484691A1
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
By recognizing that impaired endothelium-dependent arterial vasomotor response, or "endothelial dysfunction", is the central manifestation of both established and pre-clinical atherosclerosis, a nutritional composition has been invented. The composition provides a novel mixture of ingredients each one of which having been chosen on the basis of its demonstrated ability to reverse endothelial dysfunction in individuals suffering from a disease of atherosclerosis or in individuals who are disease-free but carry at least one risk factor for atherosclerosis. The composition consists of pharmacological doses of folic acid, niacin, vitamin C, vitamin E, coenzyme Q, omega-3 polyunsaturated fatty acids, and magnesium salt. It is recognized that any individual who, unpredictably, may be refractory to one or more of the aforementioned agents will likely be responsive to the other agents and thereby receive benefit from the composition as a whole. Furthermore, individuals who are responsive to more than one agent, or all the agents, will enjoy particular benefit from the composition by virtue of the additive effects of the individual agents. Thus, by reversing endothelial dysfunction in at-risk, disease-free individuals, the earliest step of atherogenesis can be blocked and disease development can be prevented; and, by treating individuals afflicted with any one of the diseases of atherosclerosis - coronary artery disease, cerebrovascular disease or peripheral vascular disease - the chance of ischemic attacks can be reduced.
Description
A NUTRICEUTICAL COMPOSITION FOR THE CORRECTION OF IMPAIRED
ENDOTHELIUM-DEPENDENT ARTERIAL VASOMOTOR RESPONSE
SPECIFICATION
Technical Field of the Invention This invention pertains to a composition of nutritional elements that have been specifically chosen to be mixed in specific proportions in order to provide a particular daily dose, or dose range, for the purpose of reversing impaired endothelium-dependent arterial vasomotor response, or "endothelial dysfunction". The vascular endothelium is a single cell layer comprising the inner wall of blood vessels. Underneath the endothelial layer is the layer of smooth muscle cells which, upon contraction, cause the constriction of the blood vessel lumen, and upon relaxing, brings about its vasodilation. One of the critical functions of the endothelial layer, upon sensing blood flow shear stress, or other stimuli, such as acetylcholine, is to signal to the smooth muscle cells to relax, thereby increasing the blood vessel's diameter in order to accommodate the increased demands of rapid blood flow. When this vasomotor response of the arterial endothelium fails to occur, or worse, is even reversed - that is, responding instead with vasoconstriction - then the endothelium-dependent arterial vasomotor response is said to be impaired.
The endothelial layer is also responsible for other functions: By the inhibiting of leukocyte adhesion to the endothelium and of smooth muscle cell proliferation, it prevents inflammatory processes from occurring in blood vessel walls. It has an anti-coagulant influence by virtue of its inhibition of platelet aggregation and its promotion of fibrinolysis. Impaired endothelial functioning manifests a failure also of these actions, resulting in the accumulation and proliferation of cell mass in the blood vessel wall. Monocyte leukocytes, attracted into the interstices of the blood vessel wall and transformed into macrophages, become engorged with oxidized low density lipoprotein (LDL) cholesterol and, having become immobilized there, form the major cellular component of the atherosclerotic plaque, or atheroma. The blood vessel wall becomes thickened at the expense of lumen volume, and, with a diminished lumen volume (stenosis), blood flow is constricted. The constriction to blood flow is called ischemia. If an increased blood supply is needed for, say, the heart's myocardium during vigorous exercise, the constriction to blood flow in the narrowed coronary artery vessels will prevent a sufficient supply of oxygen to the taxed heart. Further, if proper vasomotor response to the increased blood flow is absent, vasodilation for the purpose of accommodating the increased blood flow will not occur, further taxing the heart. The painful clinical manifestation of this state of affairs is termed angina pectoris. Atherosclerotic occlusion of the arteries in the leg can also occur and it results in intermittent claudication, muscle pain that limits walking. (1-3) In advanced atherosclerosis, the atherosclerotic plaque may rupture due to mechanical flow stresses or oxidative degradation of the plaque coating. The exposed atheroma attracts platelets which aggregate and adhere to the site of rupture producing a thrombus.
Occurring in the coronary artery, thrombosis can block blood supply to the heart myocardium with resulting myocardial cell death (myocardial infarction). A patch of dead myocardial tissue breaks electrical contiguity and communication in the myocardium and the heart thereby fails to contract synchronously. Arrhythmias may set in. If a significant region of the myocardium is affected, effective blood pumping no longer occurs, resulting in congestive heart failure. Atherosclerosis in the arteries to the brain can lead to cerebrovascular disease and, when an atherosclerotic plaque ruptures causing blockage within the arteries supplying the brain, a stroke occurs, which entails brain cell death due to oxygen deprivation.(4) Clinical researchers have demonstrated by angiography that the locus of failed vasomotor response in subjects bearing one or more of the risk factors for atherosclerotic disease, but who are otherwise healthy, is the site years later of atherosclerotic stenosis.
This implies that endothelial dysfunction is not only a hallmark of fully entrenched atherosclerosis, but is also an early warning sign and a predictor of future disease.(5,6) It is, therefore, a desideratum not only to treat endothelial dysfunction in patients diagnosed with any of the diseases caused by atherosclerosis, but also in healthy, asymptomatic individuals who are at risk.
ENDOTHELIUM-DEPENDENT ARTERIAL VASOMOTOR RESPONSE
SPECIFICATION
Technical Field of the Invention This invention pertains to a composition of nutritional elements that have been specifically chosen to be mixed in specific proportions in order to provide a particular daily dose, or dose range, for the purpose of reversing impaired endothelium-dependent arterial vasomotor response, or "endothelial dysfunction". The vascular endothelium is a single cell layer comprising the inner wall of blood vessels. Underneath the endothelial layer is the layer of smooth muscle cells which, upon contraction, cause the constriction of the blood vessel lumen, and upon relaxing, brings about its vasodilation. One of the critical functions of the endothelial layer, upon sensing blood flow shear stress, or other stimuli, such as acetylcholine, is to signal to the smooth muscle cells to relax, thereby increasing the blood vessel's diameter in order to accommodate the increased demands of rapid blood flow. When this vasomotor response of the arterial endothelium fails to occur, or worse, is even reversed - that is, responding instead with vasoconstriction - then the endothelium-dependent arterial vasomotor response is said to be impaired.
The endothelial layer is also responsible for other functions: By the inhibiting of leukocyte adhesion to the endothelium and of smooth muscle cell proliferation, it prevents inflammatory processes from occurring in blood vessel walls. It has an anti-coagulant influence by virtue of its inhibition of platelet aggregation and its promotion of fibrinolysis. Impaired endothelial functioning manifests a failure also of these actions, resulting in the accumulation and proliferation of cell mass in the blood vessel wall. Monocyte leukocytes, attracted into the interstices of the blood vessel wall and transformed into macrophages, become engorged with oxidized low density lipoprotein (LDL) cholesterol and, having become immobilized there, form the major cellular component of the atherosclerotic plaque, or atheroma. The blood vessel wall becomes thickened at the expense of lumen volume, and, with a diminished lumen volume (stenosis), blood flow is constricted. The constriction to blood flow is called ischemia. If an increased blood supply is needed for, say, the heart's myocardium during vigorous exercise, the constriction to blood flow in the narrowed coronary artery vessels will prevent a sufficient supply of oxygen to the taxed heart. Further, if proper vasomotor response to the increased blood flow is absent, vasodilation for the purpose of accommodating the increased blood flow will not occur, further taxing the heart. The painful clinical manifestation of this state of affairs is termed angina pectoris. Atherosclerotic occlusion of the arteries in the leg can also occur and it results in intermittent claudication, muscle pain that limits walking. (1-3) In advanced atherosclerosis, the atherosclerotic plaque may rupture due to mechanical flow stresses or oxidative degradation of the plaque coating. The exposed atheroma attracts platelets which aggregate and adhere to the site of rupture producing a thrombus.
Occurring in the coronary artery, thrombosis can block blood supply to the heart myocardium with resulting myocardial cell death (myocardial infarction). A patch of dead myocardial tissue breaks electrical contiguity and communication in the myocardium and the heart thereby fails to contract synchronously. Arrhythmias may set in. If a significant region of the myocardium is affected, effective blood pumping no longer occurs, resulting in congestive heart failure. Atherosclerosis in the arteries to the brain can lead to cerebrovascular disease and, when an atherosclerotic plaque ruptures causing blockage within the arteries supplying the brain, a stroke occurs, which entails brain cell death due to oxygen deprivation.(4) Clinical researchers have demonstrated by angiography that the locus of failed vasomotor response in subjects bearing one or more of the risk factors for atherosclerotic disease, but who are otherwise healthy, is the site years later of atherosclerotic stenosis.
This implies that endothelial dysfunction is not only a hallmark of fully entrenched atherosclerosis, but is also an early warning sign and a predictor of future disease.(5,6) It is, therefore, a desideratum not only to treat endothelial dysfunction in patients diagnosed with any of the diseases caused by atherosclerosis, but also in healthy, asymptomatic individuals who are at risk.
At the crossroads of all these manifestations of endothelial dysfunction lies the gaseous signaler, nitric oxide (NO), and the enzyme that produces it, endothelial nitric oxide synthase (eNOS).
Nitric oxide signals smooth muscle cells to relax; inhibits the expression on endothelial cell surfaces of vascular cell adhesion molecules, which are the "anchors" by which monocyte leukocytes and platelets adhere to the endothelium; and it inhibits the proliferation of smooth muscle cells. Nitric oxide is, hence, anti-atherogenic, and diminished bio-availability of nitric oxide results in pro-atherogenic endothelial dysfunction - in all its manifestations. It has been observed that the risk factors for atheroselerosis - dyslipidemia, hyperhomocyst(e)inemia, hypertension, diabetes, cigarette smoking - are associated with endothelial dysfunction and with oxidative stress in the environment of the endothelium. This oxidative stress is the likely cause of the impaired eNOS bio-availability, presumably due to increased oxidative destruction of NO
and the inactivation of endothelial nitric oxide synthase. (7) Notwithstanding the aforementioned explanatory mechanism for endothelial dysfunction which centres on the mediation of nitric oxide and the functioning of endothelial nitric oxide synthase, the claims of this invention do not rely on that mechanism, nor on any other mechanism, but rather, on the empirical evidence alone that the fact of the reversal of impaired arterial vasomotor response is effected by the administering of the ingredients of the invention's composition, as described below.
References to Technical Field of the Invention (1) "Atherogenic Lipids and Endothelial Dysfunction: Mechanisms in the Genesis of Ischemic Syndromes" by Adams, M.A., et al. in Annu. Rev. Med. 51:149-167, 2000.
(2) "Endothelial Dysfunction: A Marker for Atherosclerosis Risk" by Bonetti.
PØ, Lerman, L.O. and Lerman, A. in Arterioscler. Thromb. Vasc. Biol. 22:1065-1074, 2003.
Nitric oxide signals smooth muscle cells to relax; inhibits the expression on endothelial cell surfaces of vascular cell adhesion molecules, which are the "anchors" by which monocyte leukocytes and platelets adhere to the endothelium; and it inhibits the proliferation of smooth muscle cells. Nitric oxide is, hence, anti-atherogenic, and diminished bio-availability of nitric oxide results in pro-atherogenic endothelial dysfunction - in all its manifestations. It has been observed that the risk factors for atheroselerosis - dyslipidemia, hyperhomocyst(e)inemia, hypertension, diabetes, cigarette smoking - are associated with endothelial dysfunction and with oxidative stress in the environment of the endothelium. This oxidative stress is the likely cause of the impaired eNOS bio-availability, presumably due to increased oxidative destruction of NO
and the inactivation of endothelial nitric oxide synthase. (7) Notwithstanding the aforementioned explanatory mechanism for endothelial dysfunction which centres on the mediation of nitric oxide and the functioning of endothelial nitric oxide synthase, the claims of this invention do not rely on that mechanism, nor on any other mechanism, but rather, on the empirical evidence alone that the fact of the reversal of impaired arterial vasomotor response is effected by the administering of the ingredients of the invention's composition, as described below.
References to Technical Field of the Invention (1) "Atherogenic Lipids and Endothelial Dysfunction: Mechanisms in the Genesis of Ischemic Syndromes" by Adams, M.A., et al. in Annu. Rev. Med. 51:149-167, 2000.
(2) "Endothelial Dysfunction: A Marker for Atherosclerosis Risk" by Bonetti.
PØ, Lerman, L.O. and Lerman, A. in Arterioscler. Thromb. Vasc. Biol. 22:1065-1074, 2003.
(3) "Endothelium and the Lipid Metabolism: The Current Understanding" by Laroia, S.T. et al. in International Journal of Cardiology 88:1-9, 2003.
(4) "Inflammation and Atherothrombosis" by Robbie, L. and Libby, P. in Ann.
N.Y. Acad. Sci.
947:167-180, Dec. 2001.
N.Y. Acad. Sci.
947:167-180, Dec. 2001.
(5) "Prognostic Impact of Coronary Vasodilator Dysfunction in Adverse Long-Term Outcome of Coronary Heart Disease" by Schachinger, V. et al. in Circulation 101:1899-1906, 2000.
(6) "Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction: A Marker of Atherosclerosis Risk" by Bonetti, P.O., Lerman, L.O.
and Lerman, A. in Arterioscler. Thromb. Vasc. Biol. 23:168-175, 2003.
and Lerman, A. in Arterioscler. Thromb. Vasc. Biol. 23:168-175, 2003.
(7) "Endothelial Dysfunction in Cardiovascular Disease: The Role of Oxidant Stress" by Cai, H.
and Harrison, D.G. in Circulation Research x:840-844, 2000.
Background Art A functional food product, called "HeartBarTm" (Unither Pharma, Silver Spring, MD, U.S.A.), contains a nutritional formulation intended to correct endothelial dysfunction in patients with the diseases of atherosclerosis. The key ingredient in HeartBarT'" is L-arginine, the substrate of endothelial nitric oxide synthase (eNOS), and is supplied in up to six grams per bar. It is recommended that two bars per day be ingested for effective treatment.
HeartBarTm is protected by U.S. patent 6,063,432, "Arginine or Lysine Containing Fruit HealthBar Formulation". This product is based on published research that has demonstrated that, by promoting eNOS activity, L-arginine can reverse endothelial dysfunction in patients with coronary artery disease, stable angina and heart failure, and in healthy subjects with the risk factors for atherosclerosis:
hypercholesterolemia, hypertension, advanced age, smoking, and diabetes.( 1 ) The reality, however, is that results with arginine supplementation are inconsistent.
Negative results with arginine have been reported in coronary artery disease (2); stable angina (3), and heart failure (4).
The contradictory results with arginine supplementation is paralleled by contradictory reports on HeartBarTm itself-. Positive results with HeartBarTm (5,6) stand in contrast with negative results (7). It has been suggested that not enough is known about the complexities of eNOS to recommend arginine's use, and that the catabolic relationship between arginine and the competitive inhibitor of eNOS, asymmetric dimethylarginine (ADMA), may result in opposing, undesirable results.(8) The use of arginine in combination with HMG-CoA reductase inhibitors (statins) in the treatment of the diseases of atherosclerosis by promoting nitric oxide synthesis is described in Canadian patent CA2286671, "Method and Formulation for Treating Vascular Disease". The use of arginine and derivatives of arginine is claimed in Canadian patent CA2404909, "Pharmacotherapy for Vascular Dysfunction Associated with Deficient Nitric Oxide Bioactivity".
These would also have to contend with the inconsistent clinical findings as described above.
A practical disadvantage to arginine therapy is that, because of the large amounts required - about grams per day - a large number of pills must be taken each day. To avoid that inconvenience, 10 the arginine can be provided in alternate dosage forms, for instance, in a drink powder or a nutritional "snack bar".
An alternative to both the inconsistent clinical trials with arginine and the practical restrictions to dosage forms is to seek out other nutritional modulators of endothelial function.
References to Background Art ( 1 ) "Arginine Nutrition and Cardiovascular Function" by Wu, G. and Meininger, C.J. in J. Nutr.
130:2626-2629, 2000.
(2) "Oral L-Arginine in Patients With Coronary Artery Disease on Medical Management" by Blum, A. et al. in Circulation 101:2160-2164, 2000.
(3) "Endothelium-dependent Vasodilation is Independent of the Plasma L-Arginine/ADMA
Ratio in Men With Stable Angina: Lack of Effect of Oral L-Arginine on Endothelial Function, Oxidative Stress and Exercise Performance" by Walker, H.A. et al. in M. Am.
Coll. Cardiol. 38(2):499-505, 2001.
(4) "Dietary Supplementation With L-Arginine Fails To Restore Endothelial Function in Forearm Resistance Arteries of Patients with Severe Heart Failure" by Chin-Dusting, J.P. et al. in J. Am. Coll. Cardiol. 27(5):1207-1213; 1996.
(5) "Nutritional Therapy For Peripheral Arterial Disease: A Double-blind, Placebo-controlled, Randomized Trial of HeartBar" by Maxwell, A.J., Anderson, B.E. and Cooke, J.P.
in Vasc. Med. 5_(1):11-19, 2000.
(6) "Randomized Trial of a Medical Food for the Dietary Management of Chronic, Stable Angina" by Maxwell, A.J. et al. in J. Am. Coll. Cardiol. 39:37-45, 2002.
(7) "No Effect of an L-Arginine-enriched Medical Food (HeartBars) on Endothelial Function and Platelet Aggregation in Subjects with Hypercholesterolemia" by Abdelhamed, A.I. et al.
in Am. Heart. J. 145(3):E15, Mar. 2003.
and Harrison, D.G. in Circulation Research x:840-844, 2000.
Background Art A functional food product, called "HeartBarTm" (Unither Pharma, Silver Spring, MD, U.S.A.), contains a nutritional formulation intended to correct endothelial dysfunction in patients with the diseases of atherosclerosis. The key ingredient in HeartBarT'" is L-arginine, the substrate of endothelial nitric oxide synthase (eNOS), and is supplied in up to six grams per bar. It is recommended that two bars per day be ingested for effective treatment.
HeartBarTm is protected by U.S. patent 6,063,432, "Arginine or Lysine Containing Fruit HealthBar Formulation". This product is based on published research that has demonstrated that, by promoting eNOS activity, L-arginine can reverse endothelial dysfunction in patients with coronary artery disease, stable angina and heart failure, and in healthy subjects with the risk factors for atherosclerosis:
hypercholesterolemia, hypertension, advanced age, smoking, and diabetes.( 1 ) The reality, however, is that results with arginine supplementation are inconsistent.
Negative results with arginine have been reported in coronary artery disease (2); stable angina (3), and heart failure (4).
The contradictory results with arginine supplementation is paralleled by contradictory reports on HeartBarTm itself-. Positive results with HeartBarTm (5,6) stand in contrast with negative results (7). It has been suggested that not enough is known about the complexities of eNOS to recommend arginine's use, and that the catabolic relationship between arginine and the competitive inhibitor of eNOS, asymmetric dimethylarginine (ADMA), may result in opposing, undesirable results.(8) The use of arginine in combination with HMG-CoA reductase inhibitors (statins) in the treatment of the diseases of atherosclerosis by promoting nitric oxide synthesis is described in Canadian patent CA2286671, "Method and Formulation for Treating Vascular Disease". The use of arginine and derivatives of arginine is claimed in Canadian patent CA2404909, "Pharmacotherapy for Vascular Dysfunction Associated with Deficient Nitric Oxide Bioactivity".
These would also have to contend with the inconsistent clinical findings as described above.
A practical disadvantage to arginine therapy is that, because of the large amounts required - about grams per day - a large number of pills must be taken each day. To avoid that inconvenience, 10 the arginine can be provided in alternate dosage forms, for instance, in a drink powder or a nutritional "snack bar".
An alternative to both the inconsistent clinical trials with arginine and the practical restrictions to dosage forms is to seek out other nutritional modulators of endothelial function.
References to Background Art ( 1 ) "Arginine Nutrition and Cardiovascular Function" by Wu, G. and Meininger, C.J. in J. Nutr.
130:2626-2629, 2000.
(2) "Oral L-Arginine in Patients With Coronary Artery Disease on Medical Management" by Blum, A. et al. in Circulation 101:2160-2164, 2000.
(3) "Endothelium-dependent Vasodilation is Independent of the Plasma L-Arginine/ADMA
Ratio in Men With Stable Angina: Lack of Effect of Oral L-Arginine on Endothelial Function, Oxidative Stress and Exercise Performance" by Walker, H.A. et al. in M. Am.
Coll. Cardiol. 38(2):499-505, 2001.
(4) "Dietary Supplementation With L-Arginine Fails To Restore Endothelial Function in Forearm Resistance Arteries of Patients with Severe Heart Failure" by Chin-Dusting, J.P. et al. in J. Am. Coll. Cardiol. 27(5):1207-1213; 1996.
(5) "Nutritional Therapy For Peripheral Arterial Disease: A Double-blind, Placebo-controlled, Randomized Trial of HeartBar" by Maxwell, A.J., Anderson, B.E. and Cooke, J.P.
in Vasc. Med. 5_(1):11-19, 2000.
(6) "Randomized Trial of a Medical Food for the Dietary Management of Chronic, Stable Angina" by Maxwell, A.J. et al. in J. Am. Coll. Cardiol. 39:37-45, 2002.
(7) "No Effect of an L-Arginine-enriched Medical Food (HeartBars) on Endothelial Function and Platelet Aggregation in Subjects with Hypercholesterolemia" by Abdelhamed, A.I. et al.
in Am. Heart. J. 145(3):E15, Mar. 2003.
(8) "Adverse Effects of Supplemental L-Arginine in Atherosclerosis:
Consequences of Methylation Stress in a Complex Catabolism?" by Loscalzo, J. in Arterioscler.
Thromb.
Vasc. Biol. 23: 3-5, 2003.
Disclosure of the Invention Of the various functions associated with a healthy endothelium - arterial vasomotor dilation and inhibitory control of coagulation and inflammatory processes - as described above in "Technical Field of the Invention", the easiest activity to monitor clinically is arterial vasodilation. It has been shown that a reliable proxy for coronary artery vasomotor dilation is that of the brachial artery, which means that experiments can be done non-invasively. In one technique that measures vasomotor response, the brachial artery diameter is monitored by ultrasound imaging before (baseline) and after inducing rapid blood flow. Rapid blood flow is induced by applying a pneumatic tourniquet on the lower arm beyond the position of the ultrasound transducers and then suddenly releasing it, thereby producing reactive hyperemia in the artery.(1) This technique is called Flow Mediated Dilatation (FMD). Healthy vasomotor response to hyperemia amounts, approximately, to a 12% increase in arterial diameter.(2) Individuals with proven coronary artery disease are measured to have an average FMD response of 3% with a large inter-subject variability that even encompasses null vasodilation response in some patients.(3) Individuals that are otherwise healthy but who bear (a) risk factors) for atherosclerosis manifest FMD responses intermediate to these values. Improvements to FMD response brought about by various nutritional elements are described below:
(1) "Passive Smoking and Impaired Endothelium-Dependent Arterial Dilatation in Healthy Young Adults" by Celermajer, D. et al. in The New England Journal of Medicine.
Jan.
18, 1996; 334:150-154.
{2) "ADMA and Oxidative Stress Are Responsible for Endothelial Dysfunction in Hyperhomocyst{e)inemia" by Sydow; K. et al. in Cardiovascular Research ,7:244-252, 2003.
(3) "Effect of Folic Acid and Antioxidant Vitamins on Endothelial Dysfunction in Patients With Coronary Artery Disease" by Title, L.M. et al. in Journal of the American College of IO Cardiology x_6:758-765, 2000.
Folic Acid At a folic acid dose of at least 5 mg/d impaired vasomotor response can be improved. For instance, in subjects with coronary artery disease the flow-mediated dilatation was raised from an average of 3.2% to an average of 5.2% using a dose of 5 mg.(1) Folic acid administered at a dose of I O mg/d to healthy subjects with the risk factor of hyperhomocyst(e)inemia raised endothelium-dependent vasodilation from 6% to 8.2°/a.(2) Healthy subjects with hypercholesterolemia demonstrated impaired FMD which could be reversed with S
mg/d of folic acid.(3) However, while a majority of studies found improvements in endothelial functioning following high-dose folic acid supplementation, one study reported negative results, which suggests that some, as yet uncharacterized sub-populations may not respond to folic acid.(4) An additional benefit of folic acid on endothelial dysfunction is its ability to reverse nitrate tolerance in long term users of nitroglycerin.(5) (1) "Effect of Folic Acid and Antioxidant Vitamins on Endothelial Dysfunction in Patients With Coronary Artery Disease" by Title, L.M. et al. in Journal of the American College of Cardiology 36:758-765, 2000.
(2) "Folic Acid Improves Arterial Endothelial Function in Adults With Hyperhomocystinemia"
_7_ by Woo, K.S. et al. in Journal of the American College of Cardiology 34:2002-2006, 1999.
(3) "Effects of Folic Acid Supplementation on Endothelial Function in Familial Hypercholesterolemia" by Verhaar, M.C. et al. in Circulation 100:335-338, 1999.
(4) "ADMA and Oxidative Stress Are Responsible for Endothelial Dysfunction in Hyperhomocyst(e)inemia: Effects of L-Arginine and B Vitamins" by Sydow, K. et al. in Cardiovascular Research x:244-252, 2003.
(5) "Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance" by Gori. T. et al. in Circulation 104:1119-1123, 2001.
N'acin Niacin, in the form of its free acid, nicotinic acid, lowers low density lipoprotein (LDL) and raises high density lipoprotein (HDL).(1) Nicotinic acid can also be administered in its esterified forms, such as inositol hexanicotinate, since esters of nicotinic acid hydrolyze readily to the free acid form.(2,3) In line with the knowledge that LDL cholesterol, being highly susceptible to oxidation, causes injurious oxidative stress in the environment of the endothelium, endothelium-dependent arterial vasomotor function is impaired by elevated plasma LDL levels.(4) Fortunately, impaired vasomotor response in hypercholesterolemic subjects, both those with and without coronary artery disease, can be reversed by cholesterol reduction therapy. Out of 15 trials, using various lipid lowering agents including niacin, only 2 failed to show improvement.(5) High density lipoprotein (HDL), on the other hand, is protective against atherogenesis by virtue of its functioning in reverse transport of cholesterol (the main atheroma material) and of phospholipids out of the endothelium and to the liver (6), its ability to protect lipids from peroxidation, and its anti-thrombotic and anti-inflammatory activities (7). A
low plasma HDL
level is an independent risk factor for developing coronary artery disease, and low HDL levels in healthy male subjects are correlated with poor endothelial function.(8) Proving the cause and _g_ effect linkage between HDL and endothelial dysfunction is the demonstration that intravenous infusion of reconstituted HDL particles into healthy subjects with hypercholesterolemia brings about an improvement in FMD from 2.7% to 4.5%.(9) Proof that FMD can be improved nutritionally using niacin and that the improvement derives from niacin's ability to correct low S HDL levels comes from a study of coronary artery disease patients whose LDL
levels had been kept low through prior and continuing statin treatment while niacin was administered at doses of up to 1.5 mg/d. Along with raising HDL values, FMD was improved by the administered niacin to an average of 11.8% from a pretreatment average of 6.5%, and the FMD
percentage improvements of individual patients were correlated to their post-treatment plasma HDL
values.{10) (1) Compendium of Pharmaceuticals and Specialties, 34'" edition, 1999, published by Canadian Pharmacists Association, pg. 1169.
(2) "Nocturnal Inhibition of Lipolysis in Man by Nicotinic Acid and Derivatives" by Kruse, W.
et al. in Eur. J. Clin. Pharmacol. ,x_6:11-15, 1979.
(3) "Comparative Evaluation of Some Pharmacological Properties and Side Effects of D-glucitol Hexanicotinate and Nicotinic Acid Correlated With the Plasma Concentration of Nicotinic Acid" by Subissi, A. et al. in Atherosclerosis 36(1):135-148, May, 1980.
(4) "Atherogenic Lipids and Endothelial Dysfunction: Mechanisms in the Genesis of Ischemic Syndromes" by Adams, M.R. et al. in Annu. Rev. Med. 51:149-167, 2000.
(5) "Cholesterol Lowering and Endothelial Function" by Vogel R.A. in Am. J.
Med. 107:479-487, 1999.
(6) "High Density Lipoproteins and Arteriosclerosis: Role of Cholesterol Efflux and Reverse Cholesterol Transport" by von Eckardstein, A., Nofer, J-R., and Assmann, G. in Arterioscler. Thromb. Vasc. Biol. 21:13-27, 2001.
(7) "Endothelial Protection by High-Density Lipoproteins: From Bench to Bedside" by Calabresi, L., Gomaraschi, M., and Franceschini, G. in Arterioscler. Thromb. Vasc. Biol.
23:1724-1731, 2003.
(8) "Endothelial Nitric Oxide Synthase Gene Polymorphism, Homocysteine, Cholesterol and Vascular Endothelial Function" by Bilsborough, W. et al. in Atherosclerosis 169:131-138, 2003.
(9) "High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men" by Spieker, L.E. et al. in Circulation 105:1399-1402.
S (10) "A Novel Mechanism for the Beneficial Vascular Effects of High-Density Lipoprotein Cholesterol: Enhanced Vasorelaxation and Increased Endothelial Nitric Oxide Synthase Expression" by Kuvin, J.T. et al. in American Heart Journal 144:165-172, 2002.
Vitamin C
I O As stated above, in Technical Field of the Invention, oxidative stress is associated with the risk factors for atherosclerosis, and manifests itself at the molecular level with decreased bioavailability of NO, probably through oxidation of NO to nitrite and nitrate. To counteract oxidative stress, experiments have been carried out to investigate the effect on FMD of the water-soluble antioxidant, vitamin C (ascorbic acid). In the majority of clinical studies, patients with 15 coronary heart disease as well as subjects who were otherwise healthy but were at risk due to diabetes, smoking, hypercholesterolemia, and hyperhomocysteinemia had their impaired endothelial vasomotor responses improved by vitamin C. The methods of administration in these experiments consisted of oral chronic dosing at 0.5 - 2 grams per day, acute oral dosing at 2 grams, and intravenous infusion with 1-3 grams. (1-14) A minority of studies, however, failed to 20 demonstrate improvement in FMD: one study on coronary artery disease patients (15) against seven positive studies on diseased subjects; one study on healthy smokers (16}
against three successful reports on smokers; and one study on hypertensive, healthy subjects (17). (The hypertensive subjects of the last study, however, did benefit from lowered blood pressure, which is another aspect of endothelial function.) These exceptions suggest that there may be sub-25 populations, yet unrecognized, that are resistant to the otherwise beneficial effect of vitamin C.
An additional benefit of vitamin C on endothelial dysfunction is its ability to counteract tolerance adaptation to long-term, continuous use of nitroglycerin. ( 18) (1 ) "Vitamin C Improves Endothelium-dependent Vasodilation in Patients With Non-Insulin-Dependent Diabetes Mellitus" by Ting, H.H. et al. in J. Clinical Investigation 92(1):22-28, 1996.
(2) "Ascorbic Acid Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease" by Levine. G.N. et al. in Circulation 93:1107-1113, 1996.
(3) "Antioxidant Vitamin C Improves Endothelial Dysfunction in Chronic Smokers" by Heitzer, T., Just, H. and Munzel, T. in Circulation 94(1):6-9, 1996.
(4) "Vitamin C Improves Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure" by Hornig, B. et al. in Circulation 97:363-368, 1998.
(5) "Vitamin C Improves Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans With Hypercholesterolemia" by Ting. H.H. et al. in Circulation 95:2617-2622, 1997.
(6) "Long-Term Ascorbic Acid Administration Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease" by Gokce, N. et al. in Circulation 99:3234-3240, 1999.
{7) "Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia: An Effect Reversible With Vitamin C Therapy" by Chambers, J.C. et al. in Circulation 99:1156-1160, 1999.
{8) "Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans" by Kanani, P.M. et al. in Circulation 100:1161-1168, 1999.
(9) "Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease" by Heitzer, T. et al. in Circulation 104:2673-2678, 2001.
(10) "Acute Effects of Vitamin C on Platelet Responsiveness to Nitric Oxide Donors and Endothelial Function in Patients with Chronic Heart Failure" by Ellis, G.R. et al. in J.
Cardiovascular Pharmacology 37:564-570, 2001.
Consequences of Methylation Stress in a Complex Catabolism?" by Loscalzo, J. in Arterioscler.
Thromb.
Vasc. Biol. 23: 3-5, 2003.
Disclosure of the Invention Of the various functions associated with a healthy endothelium - arterial vasomotor dilation and inhibitory control of coagulation and inflammatory processes - as described above in "Technical Field of the Invention", the easiest activity to monitor clinically is arterial vasodilation. It has been shown that a reliable proxy for coronary artery vasomotor dilation is that of the brachial artery, which means that experiments can be done non-invasively. In one technique that measures vasomotor response, the brachial artery diameter is monitored by ultrasound imaging before (baseline) and after inducing rapid blood flow. Rapid blood flow is induced by applying a pneumatic tourniquet on the lower arm beyond the position of the ultrasound transducers and then suddenly releasing it, thereby producing reactive hyperemia in the artery.(1) This technique is called Flow Mediated Dilatation (FMD). Healthy vasomotor response to hyperemia amounts, approximately, to a 12% increase in arterial diameter.(2) Individuals with proven coronary artery disease are measured to have an average FMD response of 3% with a large inter-subject variability that even encompasses null vasodilation response in some patients.(3) Individuals that are otherwise healthy but who bear (a) risk factors) for atherosclerosis manifest FMD responses intermediate to these values. Improvements to FMD response brought about by various nutritional elements are described below:
(1) "Passive Smoking and Impaired Endothelium-Dependent Arterial Dilatation in Healthy Young Adults" by Celermajer, D. et al. in The New England Journal of Medicine.
Jan.
18, 1996; 334:150-154.
{2) "ADMA and Oxidative Stress Are Responsible for Endothelial Dysfunction in Hyperhomocyst{e)inemia" by Sydow; K. et al. in Cardiovascular Research ,7:244-252, 2003.
(3) "Effect of Folic Acid and Antioxidant Vitamins on Endothelial Dysfunction in Patients With Coronary Artery Disease" by Title, L.M. et al. in Journal of the American College of IO Cardiology x_6:758-765, 2000.
Folic Acid At a folic acid dose of at least 5 mg/d impaired vasomotor response can be improved. For instance, in subjects with coronary artery disease the flow-mediated dilatation was raised from an average of 3.2% to an average of 5.2% using a dose of 5 mg.(1) Folic acid administered at a dose of I O mg/d to healthy subjects with the risk factor of hyperhomocyst(e)inemia raised endothelium-dependent vasodilation from 6% to 8.2°/a.(2) Healthy subjects with hypercholesterolemia demonstrated impaired FMD which could be reversed with S
mg/d of folic acid.(3) However, while a majority of studies found improvements in endothelial functioning following high-dose folic acid supplementation, one study reported negative results, which suggests that some, as yet uncharacterized sub-populations may not respond to folic acid.(4) An additional benefit of folic acid on endothelial dysfunction is its ability to reverse nitrate tolerance in long term users of nitroglycerin.(5) (1) "Effect of Folic Acid and Antioxidant Vitamins on Endothelial Dysfunction in Patients With Coronary Artery Disease" by Title, L.M. et al. in Journal of the American College of Cardiology 36:758-765, 2000.
(2) "Folic Acid Improves Arterial Endothelial Function in Adults With Hyperhomocystinemia"
_7_ by Woo, K.S. et al. in Journal of the American College of Cardiology 34:2002-2006, 1999.
(3) "Effects of Folic Acid Supplementation on Endothelial Function in Familial Hypercholesterolemia" by Verhaar, M.C. et al. in Circulation 100:335-338, 1999.
(4) "ADMA and Oxidative Stress Are Responsible for Endothelial Dysfunction in Hyperhomocyst(e)inemia: Effects of L-Arginine and B Vitamins" by Sydow, K. et al. in Cardiovascular Research x:244-252, 2003.
(5) "Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance" by Gori. T. et al. in Circulation 104:1119-1123, 2001.
N'acin Niacin, in the form of its free acid, nicotinic acid, lowers low density lipoprotein (LDL) and raises high density lipoprotein (HDL).(1) Nicotinic acid can also be administered in its esterified forms, such as inositol hexanicotinate, since esters of nicotinic acid hydrolyze readily to the free acid form.(2,3) In line with the knowledge that LDL cholesterol, being highly susceptible to oxidation, causes injurious oxidative stress in the environment of the endothelium, endothelium-dependent arterial vasomotor function is impaired by elevated plasma LDL levels.(4) Fortunately, impaired vasomotor response in hypercholesterolemic subjects, both those with and without coronary artery disease, can be reversed by cholesterol reduction therapy. Out of 15 trials, using various lipid lowering agents including niacin, only 2 failed to show improvement.(5) High density lipoprotein (HDL), on the other hand, is protective against atherogenesis by virtue of its functioning in reverse transport of cholesterol (the main atheroma material) and of phospholipids out of the endothelium and to the liver (6), its ability to protect lipids from peroxidation, and its anti-thrombotic and anti-inflammatory activities (7). A
low plasma HDL
level is an independent risk factor for developing coronary artery disease, and low HDL levels in healthy male subjects are correlated with poor endothelial function.(8) Proving the cause and _g_ effect linkage between HDL and endothelial dysfunction is the demonstration that intravenous infusion of reconstituted HDL particles into healthy subjects with hypercholesterolemia brings about an improvement in FMD from 2.7% to 4.5%.(9) Proof that FMD can be improved nutritionally using niacin and that the improvement derives from niacin's ability to correct low S HDL levels comes from a study of coronary artery disease patients whose LDL
levels had been kept low through prior and continuing statin treatment while niacin was administered at doses of up to 1.5 mg/d. Along with raising HDL values, FMD was improved by the administered niacin to an average of 11.8% from a pretreatment average of 6.5%, and the FMD
percentage improvements of individual patients were correlated to their post-treatment plasma HDL
values.{10) (1) Compendium of Pharmaceuticals and Specialties, 34'" edition, 1999, published by Canadian Pharmacists Association, pg. 1169.
(2) "Nocturnal Inhibition of Lipolysis in Man by Nicotinic Acid and Derivatives" by Kruse, W.
et al. in Eur. J. Clin. Pharmacol. ,x_6:11-15, 1979.
(3) "Comparative Evaluation of Some Pharmacological Properties and Side Effects of D-glucitol Hexanicotinate and Nicotinic Acid Correlated With the Plasma Concentration of Nicotinic Acid" by Subissi, A. et al. in Atherosclerosis 36(1):135-148, May, 1980.
(4) "Atherogenic Lipids and Endothelial Dysfunction: Mechanisms in the Genesis of Ischemic Syndromes" by Adams, M.R. et al. in Annu. Rev. Med. 51:149-167, 2000.
(5) "Cholesterol Lowering and Endothelial Function" by Vogel R.A. in Am. J.
Med. 107:479-487, 1999.
(6) "High Density Lipoproteins and Arteriosclerosis: Role of Cholesterol Efflux and Reverse Cholesterol Transport" by von Eckardstein, A., Nofer, J-R., and Assmann, G. in Arterioscler. Thromb. Vasc. Biol. 21:13-27, 2001.
(7) "Endothelial Protection by High-Density Lipoproteins: From Bench to Bedside" by Calabresi, L., Gomaraschi, M., and Franceschini, G. in Arterioscler. Thromb. Vasc. Biol.
23:1724-1731, 2003.
(8) "Endothelial Nitric Oxide Synthase Gene Polymorphism, Homocysteine, Cholesterol and Vascular Endothelial Function" by Bilsborough, W. et al. in Atherosclerosis 169:131-138, 2003.
(9) "High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men" by Spieker, L.E. et al. in Circulation 105:1399-1402.
S (10) "A Novel Mechanism for the Beneficial Vascular Effects of High-Density Lipoprotein Cholesterol: Enhanced Vasorelaxation and Increased Endothelial Nitric Oxide Synthase Expression" by Kuvin, J.T. et al. in American Heart Journal 144:165-172, 2002.
Vitamin C
I O As stated above, in Technical Field of the Invention, oxidative stress is associated with the risk factors for atherosclerosis, and manifests itself at the molecular level with decreased bioavailability of NO, probably through oxidation of NO to nitrite and nitrate. To counteract oxidative stress, experiments have been carried out to investigate the effect on FMD of the water-soluble antioxidant, vitamin C (ascorbic acid). In the majority of clinical studies, patients with 15 coronary heart disease as well as subjects who were otherwise healthy but were at risk due to diabetes, smoking, hypercholesterolemia, and hyperhomocysteinemia had their impaired endothelial vasomotor responses improved by vitamin C. The methods of administration in these experiments consisted of oral chronic dosing at 0.5 - 2 grams per day, acute oral dosing at 2 grams, and intravenous infusion with 1-3 grams. (1-14) A minority of studies, however, failed to 20 demonstrate improvement in FMD: one study on coronary artery disease patients (15) against seven positive studies on diseased subjects; one study on healthy smokers (16}
against three successful reports on smokers; and one study on hypertensive, healthy subjects (17). (The hypertensive subjects of the last study, however, did benefit from lowered blood pressure, which is another aspect of endothelial function.) These exceptions suggest that there may be sub-25 populations, yet unrecognized, that are resistant to the otherwise beneficial effect of vitamin C.
An additional benefit of vitamin C on endothelial dysfunction is its ability to counteract tolerance adaptation to long-term, continuous use of nitroglycerin. ( 18) (1 ) "Vitamin C Improves Endothelium-dependent Vasodilation in Patients With Non-Insulin-Dependent Diabetes Mellitus" by Ting, H.H. et al. in J. Clinical Investigation 92(1):22-28, 1996.
(2) "Ascorbic Acid Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease" by Levine. G.N. et al. in Circulation 93:1107-1113, 1996.
(3) "Antioxidant Vitamin C Improves Endothelial Dysfunction in Chronic Smokers" by Heitzer, T., Just, H. and Munzel, T. in Circulation 94(1):6-9, 1996.
(4) "Vitamin C Improves Endothelial Function of Conduit Arteries in Patients With Chronic Heart Failure" by Hornig, B. et al. in Circulation 97:363-368, 1998.
(5) "Vitamin C Improves Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans With Hypercholesterolemia" by Ting. H.H. et al. in Circulation 95:2617-2622, 1997.
(6) "Long-Term Ascorbic Acid Administration Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease" by Gokce, N. et al. in Circulation 99:3234-3240, 1999.
{7) "Demonstration of Rapid Onset Vascular Endothelial Dysfunction After Hyperhomocysteinemia: An Effect Reversible With Vitamin C Therapy" by Chambers, J.C. et al. in Circulation 99:1156-1160, 1999.
{8) "Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans" by Kanani, P.M. et al. in Circulation 100:1161-1168, 1999.
(9) "Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease" by Heitzer, T. et al. in Circulation 104:2673-2678, 2001.
(10) "Acute Effects of Vitamin C on Platelet Responsiveness to Nitric Oxide Donors and Endothelial Function in Patients with Chronic Heart Failure" by Ellis, G.R. et al. in J.
Cardiovascular Pharmacology 37:564-570, 2001.
(11) "Impaired Endothelium-Dependent Vasodilation in the Brachial Artery in Variant Angina Pectoris and the Effect of Intravenous Administration of Vitamin C" by Hamabe, A. et al.
in American Journal of Cardiology 87:1154-1159, 2001.
-l I-(12) "Reversibility of Coronary Endothelial Vasomotor Dysfunction in Idiopathic Dilated Cardiomyopathy: Acute Effects of Vitamin C" by Richartz, B.M. et al. in American Journal of Cardiology 88:1001-1005, 2001.
in American Journal of Cardiology 87:1154-1159, 2001.
-l I-(12) "Reversibility of Coronary Endothelial Vasomotor Dysfunction in Idiopathic Dilated Cardiomyopathy: Acute Effects of Vitamin C" by Richartz, B.M. et al. in American Journal of Cardiology 88:1001-1005, 2001.
(13) "Taurine and Vitamin C Modify Monocyte and Endothelial Dysfunction in Young Smokers"
by Fennessy, F.M. et al. in Circulation 107:410-415, 2003.
by Fennessy, F.M. et al. in Circulation 107:410-415, 2003.
(14) "Oral Administration of Ascorbic Acid Attenuates Endothelial Dysfunction After Short-Term Cigarette Smoking" by Stamatelopoulos, K.S. et al. in International Journal of Nutrition Research 73(6):417-422, 2003.
(15) "Coronary Endothelial Dysfunction Is Not Rapidly Reversible With Ascorbic Acid" by Widlansky M.E. et al. in Free Radical Biology and Medicine 36(1):123-130, 2004.
(16) "Vitamin C Has No Effect on Endothelium-Dependent Vasomotion and Acute Endogenous Fibrinolysis in Healthy Smokers" by Pellegrini, M.P. et al. in J.
Cardiovascular Pharmacology 44(1):117-124, 2004.
Cardiovascular Pharmacology 44(1):117-124, 2004.
(17) "Effect of Ascorbic Acid Treatment On Conduit Vessel Endothelial Dysfunction in Patients With Hypertension" by Duffy, S.J. et al. in Am. J. Physiol. Heart Circ.
Physiol.
280:H528-H534, 2001.
Physiol.
280:H528-H534, 2001.
(18) "Dietary Supplement with Vitamin C Prevents Nitrate Tolerance" by Bassenge, E. et al. in J.
Clin. Invest. 102:67-71, 1998.
Vitamin E
Vitamin E is the major lipid-soluble antioxidant and is found in LDL particles where it is well-positioned to protect the cholesterol and phospholipids in the particles against oxidation.(1) This is important vis a vis endothelial function because oxidized LDL induces apoptosis in cultured human endothelial cells. Indeed, when LDL is incubated with the antioxidants, vitamin C and vitamin E, apoptosis was prevented.(2) Clinical trials testing vitamin E
administration at dosages ranging from 300 to 1,200 IU per day, both on subjects with heart disease and on otherwise healthy subjects with risk factors for atherosclerosis, revealed mixed results: One half of these studies demonstrated improved endothelial functioning.(3) One possible explanation for the negative findings is that some risk factors, such as smoking, cannot be compensated for with vitamin E; though it can be compensated for with vitamin C (See above, under Vitamin C,).
Another possibility is that within one risk factor category there exist different sub-populations, some of which are benefitted by vitamin E, while the others are not.
Vitamin E also has the positive effect on endothelial dysfunction in terms of its ability to counteract tolerance adaptation to long-term, continuous use of nitroglycerin.(4) (1) "Vitamin E and Heart Disease: Basic Science To Clinical Investigation Trials" by Pryor, W.A. in Free Radical Biology & Medicine x(1):141-164, 2000.
(2) "Vascular Thrombogenicity Induced by Progressive LDL Oxidation: Protection by Antioxidants" by Banfi, C. et al. in Thromb. Haemost. 89:544-SS3, 2003.
(3) "Effect of Anti-oxidant Treatment and Cholesterol Lowering On Resting Arterial Tone, Metabolic Vasodilation and Endothelial Function in the Human Forearm" by Duffy, S.J.
et al. in Clinical and Experimental Pharmacology and Physiology 28:409-418, 2001.
I S (4) "Randomized, Double-Blind, Placebo-Controlled Study of Supplemental Vitamin E on Attenuation of the Development of Nitrate Tolerance" by Watanabe, H. et al. in Circulation 96:2545-2550, 1997.
Coenzyme O
As stated above, in Technical Field of the Invention, oxidative stress, impaired eNOS activity and the risk factors for atherosclerosis are tied together in cause-and-effect relationships.
Coenzyme Q10 is a strong antioxidant and it has been shown, at a dose of 200 mg per day, to mildly improve endothelial dysfunction in dyslipidemic patients with Type II
diabetes.(I) In another study, coenzyme Q10, also at 200 mg per day, but in combination with the lipid lowering agent, fenofibrate, brought about a marked improvement in vasodilation response.(2) (1) "Coenzyme Q10 Improves Endothelial Dysfunction of the Brachial Artery in Type II Diabetes Mellitus" by Watts, G.F. et al. in Diabetologia 45:420-426, 2002.
(2) "Combined Effect of Coenzyme Ql O and Fenofibrate on Forearm Microcirculatory Function in Type 2 Diabetes" by Playford, D.A. et al. in Atherosclerosis I68(1):169-179, 2003.
Omega-3 Polyunsaturated Fatt~Aqids (,n-3 PUFAI
Both in vitro (1) and in vivo research (2,3) have demonstrated that supplementation with fish oil, S as a source of the omega-3 fatty acids, DHA (docosahexa.enoic acid) and EHA
(eicosapentaenoic acid), can significantly improve vasomotor impairment due to hypercholesterolemia. After four months of supplementation, flow mediated dilatation was raised from the pretreatment percentage diameter increase of 1:2% to 3.0% (calculated from Table 2 of Reference 3). The mechanism of the effect has not been determined, but it may be due to the altering of endothelial cell membrane fluidity and its subsequent favourable influence on eNOS
activity when the omega-3 polyunsaturated fatty acids are incorporated into the endothelial cell membranes.
(1) "Dietary Supplementation With Marine Fish Oil Improves In Vitro Small Artery Endothelial Function in Hypercholesterolemic Patients" by Goode, G.K., Garcia, S. and Heagerty, A.N. in Circulation 96:2802-2807, 1997.
(2) "Therapeutic Restoration of Endothelial Function in Hypercholesterolemic Subjects: Effects of Fish Oil" by Chin, J.P. and Dart; A.M. in Clin. Exp. Pharmacol. Physiol.
21(10):749-755, 1994.
(3) "Dietary Supplementation With Marine Omega-3 Fatty Acids Improve Systemic Large Artery Endothelial Function in Subjects With Hypercholesterolemia" by Goodfellow, J.
et al. in Journal of the American College of Cardiology ,~S_:265-270, 2000.
Magnesium By means of a mechanism that is yet to be established, endothelium-dependent vasodilation can be enhanced in healthy, young subjects by infusing magnesium salt ( 1 ) and in patients with coronary artery disease by means of oral adminstration of magnesium (2).
{ 1 ) "Magnesium Infusion Improves Endothelium-Dependent Vasodilation in the Human Forearm" by Haenni, A. et al. in American Journal of Hypertension 15:10-15, 2002.
(2) "Oral Magnesium Therapy Improves Endothelial Function in Patients With Coronary Artery Disease" by Shechter, M. et al. in Circulation X02:2353-2358, 2000.
The utility of the invention inheres in the fact that it is a combination product. Any individual whose endothelial dysfunction is not reversed by one component of the combination - a possibility realized in about one half of the trials with vitamin E and in a minority of trials using folic acid and vitamin C - may gain benefit from any one or more of the other components that are active in that individual. That individual may belong to a sub-population within a population bearing a common risk factor but which is refractory, for some yet unknown reason, to one or more of the agents while being responsive to the others. Since we cannot identify who is a member of such a sub-population, a complete combination product which includes all potentially active compounds "hedges our bets" and promises a measure of success.
Combination therapy also makes possible additive effects in individuals who are responsive, but only partially so, to each of several components. For instance, we have seen that endothelial dysfunction can be partially corrected in hypercholesterolemic individuals by lowering cholesterol with niacin. We have also seen that there are a number of agents that correct endothelial dysfunction in hypercholesterolemic subjects without altering lipid profiles; that is, the patients remain hypercholesterolemic throughout the treatment. However, if the treatment regimen includes niacin, then partial correction of endothelial dysfunction will be accomplished by virtue of LDL cholesterol lowering, and the residual endothelial dysfunction, which is left uncorrected due to incomplete cholesterol lowering, will be subsequently corrected by the other agents which operate in a hypercholesterolemic environment.
In addition to such additive effects, the possibility also exists of synergy of action, that is, when the overall effect of the mixture is determined by the multiplication of individual effects. It is known that ingestion of large amounts of arginine, the substrate of eNOS, results in improved endothelial vasomotor functioning in responding individuals. The more arginine, the faster is NO
production. (See above under Background Art.) If other agents are added, specifically, those of this invention which act either by increasing the biosynthesis of the enzyme or by switching the inactive into the active form of the enzyme, that would be effectively the same as increasing the enzyme's concentration. Hence, the net increase in NO production is determined by multiplying the fractional increase in active enzyme concentration by the fractional increase in substrate concentration. From these theoretical considerations, the administration of the composition of this invention together with large amounts of arginine could result in a powerful synergistic improvement on endothelial vasomotor functioning.
Any synergy of action that may exist among the ingredients of the invention itself, however, cannot be predicted for the reason that we lack knowledge concerning the detailed mechanisms of action of all of the individual ingredients. In any case, the utility of the invention does not depend on the ingredients' mechanisms of action but rather on the purely empirical findings of their efficacy in human subjects.
It is expected that this invention, by being capable of reversing impaired endothelium-dependent arterial vasomotor response in at-risk, disease-free individuals, can block the earliest step of atherogenesis and thereby prevent disease development. In addition to its utility in primary prevention, by treating individuals with any one of the diseases of atherosclerosis, namely, coronary artery disease, cerebrovascular disease or peripheral vascular disease, the chance of ischemic attacks can be reduced. Hence, it has utility also in secondary intervention.
A Preferred Mode of Executing the Invention The following table suggests a preferred, but not limiting, embodiment of the invention:
COMPOUND DAILY DOSE
Folic acid 5 milligrams Inositol hexanicotinate 2.2 grams (2 grams niacin equivalents) Vitamin C 1.0 gram Vitamin E 400 International Units Coenzyme Q 10 120 milligrams Fish oil concentrate 48/25 (73% 1.37 grams (1.0 gram n-3 PUFA) n-3 PUFA) Magnesium oxide 1.21 grams (730 milligrams Mg) _1~_
Clin. Invest. 102:67-71, 1998.
Vitamin E
Vitamin E is the major lipid-soluble antioxidant and is found in LDL particles where it is well-positioned to protect the cholesterol and phospholipids in the particles against oxidation.(1) This is important vis a vis endothelial function because oxidized LDL induces apoptosis in cultured human endothelial cells. Indeed, when LDL is incubated with the antioxidants, vitamin C and vitamin E, apoptosis was prevented.(2) Clinical trials testing vitamin E
administration at dosages ranging from 300 to 1,200 IU per day, both on subjects with heart disease and on otherwise healthy subjects with risk factors for atherosclerosis, revealed mixed results: One half of these studies demonstrated improved endothelial functioning.(3) One possible explanation for the negative findings is that some risk factors, such as smoking, cannot be compensated for with vitamin E; though it can be compensated for with vitamin C (See above, under Vitamin C,).
Another possibility is that within one risk factor category there exist different sub-populations, some of which are benefitted by vitamin E, while the others are not.
Vitamin E also has the positive effect on endothelial dysfunction in terms of its ability to counteract tolerance adaptation to long-term, continuous use of nitroglycerin.(4) (1) "Vitamin E and Heart Disease: Basic Science To Clinical Investigation Trials" by Pryor, W.A. in Free Radical Biology & Medicine x(1):141-164, 2000.
(2) "Vascular Thrombogenicity Induced by Progressive LDL Oxidation: Protection by Antioxidants" by Banfi, C. et al. in Thromb. Haemost. 89:544-SS3, 2003.
(3) "Effect of Anti-oxidant Treatment and Cholesterol Lowering On Resting Arterial Tone, Metabolic Vasodilation and Endothelial Function in the Human Forearm" by Duffy, S.J.
et al. in Clinical and Experimental Pharmacology and Physiology 28:409-418, 2001.
I S (4) "Randomized, Double-Blind, Placebo-Controlled Study of Supplemental Vitamin E on Attenuation of the Development of Nitrate Tolerance" by Watanabe, H. et al. in Circulation 96:2545-2550, 1997.
Coenzyme O
As stated above, in Technical Field of the Invention, oxidative stress, impaired eNOS activity and the risk factors for atherosclerosis are tied together in cause-and-effect relationships.
Coenzyme Q10 is a strong antioxidant and it has been shown, at a dose of 200 mg per day, to mildly improve endothelial dysfunction in dyslipidemic patients with Type II
diabetes.(I) In another study, coenzyme Q10, also at 200 mg per day, but in combination with the lipid lowering agent, fenofibrate, brought about a marked improvement in vasodilation response.(2) (1) "Coenzyme Q10 Improves Endothelial Dysfunction of the Brachial Artery in Type II Diabetes Mellitus" by Watts, G.F. et al. in Diabetologia 45:420-426, 2002.
(2) "Combined Effect of Coenzyme Ql O and Fenofibrate on Forearm Microcirculatory Function in Type 2 Diabetes" by Playford, D.A. et al. in Atherosclerosis I68(1):169-179, 2003.
Omega-3 Polyunsaturated Fatt~Aqids (,n-3 PUFAI
Both in vitro (1) and in vivo research (2,3) have demonstrated that supplementation with fish oil, S as a source of the omega-3 fatty acids, DHA (docosahexa.enoic acid) and EHA
(eicosapentaenoic acid), can significantly improve vasomotor impairment due to hypercholesterolemia. After four months of supplementation, flow mediated dilatation was raised from the pretreatment percentage diameter increase of 1:2% to 3.0% (calculated from Table 2 of Reference 3). The mechanism of the effect has not been determined, but it may be due to the altering of endothelial cell membrane fluidity and its subsequent favourable influence on eNOS
activity when the omega-3 polyunsaturated fatty acids are incorporated into the endothelial cell membranes.
(1) "Dietary Supplementation With Marine Fish Oil Improves In Vitro Small Artery Endothelial Function in Hypercholesterolemic Patients" by Goode, G.K., Garcia, S. and Heagerty, A.N. in Circulation 96:2802-2807, 1997.
(2) "Therapeutic Restoration of Endothelial Function in Hypercholesterolemic Subjects: Effects of Fish Oil" by Chin, J.P. and Dart; A.M. in Clin. Exp. Pharmacol. Physiol.
21(10):749-755, 1994.
(3) "Dietary Supplementation With Marine Omega-3 Fatty Acids Improve Systemic Large Artery Endothelial Function in Subjects With Hypercholesterolemia" by Goodfellow, J.
et al. in Journal of the American College of Cardiology ,~S_:265-270, 2000.
Magnesium By means of a mechanism that is yet to be established, endothelium-dependent vasodilation can be enhanced in healthy, young subjects by infusing magnesium salt ( 1 ) and in patients with coronary artery disease by means of oral adminstration of magnesium (2).
{ 1 ) "Magnesium Infusion Improves Endothelium-Dependent Vasodilation in the Human Forearm" by Haenni, A. et al. in American Journal of Hypertension 15:10-15, 2002.
(2) "Oral Magnesium Therapy Improves Endothelial Function in Patients With Coronary Artery Disease" by Shechter, M. et al. in Circulation X02:2353-2358, 2000.
The utility of the invention inheres in the fact that it is a combination product. Any individual whose endothelial dysfunction is not reversed by one component of the combination - a possibility realized in about one half of the trials with vitamin E and in a minority of trials using folic acid and vitamin C - may gain benefit from any one or more of the other components that are active in that individual. That individual may belong to a sub-population within a population bearing a common risk factor but which is refractory, for some yet unknown reason, to one or more of the agents while being responsive to the others. Since we cannot identify who is a member of such a sub-population, a complete combination product which includes all potentially active compounds "hedges our bets" and promises a measure of success.
Combination therapy also makes possible additive effects in individuals who are responsive, but only partially so, to each of several components. For instance, we have seen that endothelial dysfunction can be partially corrected in hypercholesterolemic individuals by lowering cholesterol with niacin. We have also seen that there are a number of agents that correct endothelial dysfunction in hypercholesterolemic subjects without altering lipid profiles; that is, the patients remain hypercholesterolemic throughout the treatment. However, if the treatment regimen includes niacin, then partial correction of endothelial dysfunction will be accomplished by virtue of LDL cholesterol lowering, and the residual endothelial dysfunction, which is left uncorrected due to incomplete cholesterol lowering, will be subsequently corrected by the other agents which operate in a hypercholesterolemic environment.
In addition to such additive effects, the possibility also exists of synergy of action, that is, when the overall effect of the mixture is determined by the multiplication of individual effects. It is known that ingestion of large amounts of arginine, the substrate of eNOS, results in improved endothelial vasomotor functioning in responding individuals. The more arginine, the faster is NO
production. (See above under Background Art.) If other agents are added, specifically, those of this invention which act either by increasing the biosynthesis of the enzyme or by switching the inactive into the active form of the enzyme, that would be effectively the same as increasing the enzyme's concentration. Hence, the net increase in NO production is determined by multiplying the fractional increase in active enzyme concentration by the fractional increase in substrate concentration. From these theoretical considerations, the administration of the composition of this invention together with large amounts of arginine could result in a powerful synergistic improvement on endothelial vasomotor functioning.
Any synergy of action that may exist among the ingredients of the invention itself, however, cannot be predicted for the reason that we lack knowledge concerning the detailed mechanisms of action of all of the individual ingredients. In any case, the utility of the invention does not depend on the ingredients' mechanisms of action but rather on the purely empirical findings of their efficacy in human subjects.
It is expected that this invention, by being capable of reversing impaired endothelium-dependent arterial vasomotor response in at-risk, disease-free individuals, can block the earliest step of atherogenesis and thereby prevent disease development. In addition to its utility in primary prevention, by treating individuals with any one of the diseases of atherosclerosis, namely, coronary artery disease, cerebrovascular disease or peripheral vascular disease, the chance of ischemic attacks can be reduced. Hence, it has utility also in secondary intervention.
A Preferred Mode of Executing the Invention The following table suggests a preferred, but not limiting, embodiment of the invention:
COMPOUND DAILY DOSE
Folic acid 5 milligrams Inositol hexanicotinate 2.2 grams (2 grams niacin equivalents) Vitamin C 1.0 gram Vitamin E 400 International Units Coenzyme Q 10 120 milligrams Fish oil concentrate 48/25 (73% 1.37 grams (1.0 gram n-3 PUFA) n-3 PUFA) Magnesium oxide 1.21 grams (730 milligrams Mg) _1~_
Claims (16)
1. A nutriceutical composition intended to correct impaired endothelium-dependent arterial vasomotor response in individuals with atherosclerosis and in individuals who are disease-free but are at risk for atherosclerosis wherein the ingredients consist of: folic acid or its salt, or its functionally equivalent structural derivatives or their salts; niacin in the forms either of its free acid, its salts or of its esterified derivatives;
vitamin C either as ascorbic acid or ascorbate salt; vitamin E (.alpha.-tocopherol) in any of its functionally equivalent structural variants or derivatives; coenzyme Q (ubiquinone) or any of its functionally equivalent structural derivatives or variants; a source of omega-polyunsaturated fatty acids; and magnesium salt.
vitamin C either as ascorbic acid or ascorbate salt; vitamin E (.alpha.-tocopherol) in any of its functionally equivalent structural variants or derivatives; coenzyme Q (ubiquinone) or any of its functionally equivalent structural derivatives or variants; a source of omega-polyunsaturated fatty acids; and magnesium salt.
2. The claim of 1 wherein the functionally equivalent derivatives of folic acid or of the folate salt axe its reduced forms, 7,8-dihydrofolate or tetrahydrofolate or N5-methyl-tetrahydrofolate.
3. The claim of 1 wherein the esterified derivatives of nicotinic acid may be, though not limited to, inositol hexanicotinate or D-glucitol hexanicotinate (sorbinicate) or xantinol nicotinate.
4. The claim of 1 wherein the structural variants of vitamin E include the d-or 1- stereoisomeric forms or a racemic mixture of .alpha.-tocopherol, and the structural derivatives include its esters with, but not limited to, acetic acid and succinic acid.
5. 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.
6. The claim of 1 wherein the specific omega-3 polyunsaturated fatty acids may consist of, though not restricted solely to, eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) and/or .alpha.-linolenic acid, or their alkoyl esters.
7. The claims of 1 and 6 wherein the source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or their alkoyl esters, is, though not limited to, any one or combination of fish oils, or fish oil concentrates, from mackerel, herring, salmon, tuna, trout, cod or flounder.
8. The claims of 1 and 6 wherein the source of .alpha.-linolenic acid, or its alkoyl ester(s), is, though not limited to, any one or combination of mustard seed oil, flaxseed oil, soybean oil, canola seed oil, or olive oil.
9. The claim of 1 wherein a magnesium salt may be, though not limited to, magnesium chloride, magnesium citrate, magnesium hydroxide, magnesium oxide or magnesium sulphate.
10. The claims of 1 to 9 wherein the daily dosage of folic acid or its salt, or its functionally equivalent structural derivatives or their salts, ranges from about 1 milligram to about 10 milligrams; the daily dosage of niacin in the forms either of its free acid or its salts or of its esterified derivatives ranges from about 1.5 grams to about 4 grams of niacin equivalents; the daily dosage of vitamin C either as ascorbic acid or ascorbate salt ranges from about 0.5 gram to about 3.0 grams; the daily dosage of vitamin E in any of its functionally equivalent structural variants or derivatives ranges from about 200 to about 1,200 international units (IU); the daily dosage of coenzyme Q or any of its functionally equivalent structural derivatives or variants ranges from about 50 to about milligrams; the daily dosage of omega-3 polyunsaturated fatty acids or its esters ranges from about 1 gram to 10 grams; and the daily dosage of magnesium in the magnesium salt(s) ranges from about 500 milligrams to about 2,000 milligrams.
11. The claims of 1 to 10 wherein the daily dosage of folic acid or its salt, or its functionally equivalent structural derivatives or their salts is at, or about, 5 milligrams; the daily dosage of niacin in the forms either of its free acid or its salts or of its esterified derivatives is at, or about, 2 grams of niacin equivalents; the daily dosage of vitamin C
either as ascorbic acid or ascorbate salt is at, or about, 1 gram; the daily dosage of vitamin E in any of its functionally equivalent structural variants or derivatives is at, or about, 400 international units (IU); the daily dosage of coenzyme Q or any of its functionally equivalent structural derivatives or variants is at, or about, 120 milligrams;
the daily dosage of omega-3 polyunsaturated fatty acids or its esters is at, or about, 1 gram; and the daily dosage of magnesium in the magnesium salt(s) is at, or about, 730 milligrams of magnesium.
either as ascorbic acid or ascorbate salt is at, or about, 1 gram; the daily dosage of vitamin E in any of its functionally equivalent structural variants or derivatives is at, or about, 400 international units (IU); the daily dosage of coenzyme Q or any of its functionally equivalent structural derivatives or variants is at, or about, 120 milligrams;
the daily dosage of omega-3 polyunsaturated fatty acids or its esters is at, or about, 1 gram; and the daily dosage of magnesium in the magnesium salt(s) is at, or about, 730 milligrams of magnesium.
12. The claims of 1 to 11 wherein the ingredients of the composition are available for consumption in, but not limited to, the dosage delivery forms of tablet, gel capsule, loose powder, aqueous suspension, or in a nutritional "snack bar".
13. The claims of 1 to 12 wherein the composition claimed for the correction of impaired endothelium-dependent arterial vasomotor response is part of a larger composition into which the claimed composition is mixed, wherein the additional active ingredient(s) of the larger composition is/are intended to treat the various diseases of atherosclerosis, and/or to reduce the risk factors for atherosclerosis, and/or to block other stages of atherogenesis.
14. The claims of 1 to 13 wherein the total daily dosage of the claimed composition is presented in either one unit of one of the dosage delivery forms described in claim 12, or is presented in several units of one of the dosage delivery forms of claim 12, all units of which must be taken in one day in order to achieve the prescribed daily dosage of claims and 11, and wherein the ratios of the ingredients as derivable from claims 10 and 11 are maintained within each unit of the dosage delivery form.
15. The claims of 1 and 13 wherein the diseases of atherosclerosis include, but are not limited to, coronary artery disease, cerebrovascular disease, and peripheral vascular disease.
16. The claims of 1 and 13 wherein the risk factors for atherosclerosis include dyslipidemia, hypertension, diabetes, smoking, and hyperhomocyst(e)inemia.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2006203758B2 (en) * | 2006-08-29 | 2013-12-19 | Merck & Cie | Use of folates for the prevention and treatment of vascular diseases |
US9446100B2 (en) | 2015-02-13 | 2016-09-20 | Eastern Vision Limited | Dietary supplements and formulations |
-
2004
- 2004-11-15 CA CA002484691A patent/CA2484691A1/en not_active Abandoned
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2006203758B2 (en) * | 2006-08-29 | 2013-12-19 | Merck & Cie | Use of folates for the prevention and treatment of vascular diseases |
US9446100B2 (en) | 2015-02-13 | 2016-09-20 | Eastern Vision Limited | Dietary supplements and formulations |
US10105419B2 (en) | 2015-02-13 | 2018-10-23 | Eastern Vision Limited | Dietary supplements and formulations |
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