Nutraceutical Composition And Method For Preparing The Same

FIELD OF INVENTION The present invention relates to a mouth dissolving (through oral delivery system) nutraceutical tablet and meth.od for preparing the same. More particularly the present invention relates to a mouth dissolving nutraceutical tablet and method for preparing mouth dissolving nutraceutical tablet from the extract of Beet root and hawthorn berry herbs with Sodium nitrite, Ascorbic acid, Mecobalamin and L Citrulline. Nutraceutical tablet is meant to increase or restore Nitric oxide level in the body. This is natural way to increase nitric oxide in the hody. Nitric oxide is an impmtant signaling molecule, which is required for healthy blood circulation. BACKGROUND OF THE INVENTION The mammalian biosynthesis of nitric oxide (NO) discovered in the 1980's for its roles in the immune, cardiovascular and nervous systems established a startling new paradigm in the history of l:dlular signaling mechanisms. Nitric oxide is a gas that occurs naturally throughout the body. NO is a powerful signaling molecule that causes the walls of blood vessels to relax, improving circulation. Its production by vascular endothelium is particularly important in the regulation ofblood flow. Any decrease in NO production or loss in generation ofNO due to dysfunctional vascular endothelium is a very likely cause of heart disease. Experimental and clinical studies also demonstrate that insufficient nitric oxide production. is associated with major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and atherosclerosis. llnf0rtunately, the ability to generate nitric oxide decreases with age resulting in increased risk of heart and vascular disease. Prior to this discovery, NO was widely recognized as a toxic molecule: a common air pollutant, a constituent of cigarette smoke, and a toxic gas, which appears in the exhaust of motor cars and jet airplanes, causes acid rain, and destroys the ozone layer. Thus, it was essentially inconceivable that cells would intentionally produce a toxic gas as part of normal physiology. Referring to Figure 1, NO is now recognized as one ofthe most important signaling molecules in the body, and is involved in virtually every organ system where it is responsible for modulating an astonishing variety of effects. The primary targets for NO are metals and thiols. NO can bind to soluble gualylylcyclase (sGC) and cause an increase in second messenger cGMP, and mediate a number of physiological functions. This pathway was considered the basis of NO based signaling until it was recognized that NO elicited a number of physiological and biological effects that were not dependent upon cGMP. It is now recognized that NO can react directly with thiyl radicals to form nitrosothiols or other reaction products of NO i.e., riitrite, N20 3, N20 4, which can post-translationally modify thiols to affect protein structure and function. NO has been shown to be involved in and affect practically every organ system in the body. One can then imagine a host of diseases or conditions and multi-systemic symptoms may be caused or affected by the body's dysregulation of NO production/signaling (referring to Figure 1). Maintaining NO homeostasis is critical for optimal health and disease prevention. Developing novel NO based diagnostics and therapies is central to better patient care, especially in the geriatric patient. The first pathway to be discovered for the endogenO!JS production of NO was involving Larginine, from a group of enzymes call nitriC oxide synthase (NOS). NOS enzymes produce NO by catalyzing a five electron oxidation of the guanidine nitrogen of L-arginine. Oxidation of Larginme to L-citrulline occurs via two successive mono-oxygenation reactions producing NOhydroxy- L-arginine as an intermediate. Two moles of 0 2 and 1.5 moles of nicotinamide adenine 2 dinucleotide phosphate (NADPH) are consumed per mole of NO formed. NOS enzymes are the only enzymes known to simultaneously require multiple bound cotactors/prosthetic groups: flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, glutathione, NADPH, tetrahydrobiopterin (Bfu) and Ca2+ -calmodulin. There are three isoforms of NOS, the genetic se~uence of each residing on three distinct chromosomes. One type is constitutive, Ca +/calmodulin dependent and releases NO for short time periods in response to receptor or physical stimulation. NO released by this enzyme acts as a transduction mec.hanism underlying several physiological responses. The other enzyme type is induced after activation of macrophages, endothelial cells and a numher of other cells by cytokines and once expressed, synthesizes NO for long periods of time. Furthermore, this enzyme is Ca2+ independent since calmodulin is already bound to the enzyme, and its induction is inhibited by glucocorticoids. Endothelial NOS (eNOS), neuronal NOS (nNOS) which are both constitutively express~..:d in mammalian cells have now been well characterized in the cardiovascular system and nervous system respectively, and an inducible NOS (iNOS) which was first believed to be expressed only when activated by an immune response. Now it is appreciated that eNOS is found in other cells and tissues besides the endothelium, iNOS is found constitutively in some tissues, and there are inducible forms of both eNOS and nNOS, adding confusion to the nomenclature as it was first described. In an attempt to clarify the nomenclature, the three different isoforms are now commonly referred to as NOSI, NOSH, and NOSIII for neuronal, inducible and endothelial isoforms, respectively, based on the order in which they were first purified and cloned. For years, scientists and physicians have investigated L-arginine supplementation as a means to enhance NO production. This strategy has been shown to work effectively in young healthy individuals with functional endothelium or in older patients with high levels of asymmetric C:imethyl L-arginine (ADMA) where the supplemental L-arginine could outcompete this natural inhibitor of NO production. Patients with endothelial dysfunction, however, by definition, are unable to convert L-arginine to NO and, therefore, this strategy has failed in clinical trials. Schulman et al. found that L-arginine, when added to standard post infarction therapies, did not improve vascular stiffness measurements or ejection fraction and was associated with higher post infarction mortality. L-arginine should not be recommended following acute myocardial infarction (MI). However, there are also a number of studies showing benefit to patients taking L-arginine just as many showing no benefit, no harm. Understanding the complex and complicated reaction pathway for NOS mediated production of NO from L-arginine helps us define the context for rational interventions. Using L-arginine supplementation therapy alone may not be effective due. to oxidative stress in geriatric patients rP,sulting in constittJtive NOS uncoupling by redox-based post translational modifications. Supplementing L-arginine with anti-oxidants to prevent oxidation of reduced co-factors such as BH4, might prevent NOS uncoupling and lead to better results. In a study by Taddei et al., the role of oxidative stress on NO availability and endothelial dysfunction was examined in both younger and older aged populations. They found that NO availability was profoundly restored in older patients when oxidative stress is removed by antioxidants such as vitamin C. In older individuals (age> 60 years) characterized by a profound alteration in NO availability, vitamin C not only enhanced the response to the endothelial agonist but also restoreq the inhibitory effect of L-NMMA on vasodilation to acetylcholine. Although, it is demonstrated that anti-oxidant supplementation can be very beneficial for those experiencing oxidative stress and endothelial 3 dysfunction, it showed no benefit in younger (age < 60) or healthy individuals with no endothelial dysfunction. Collectively, the literature suggests that strategies to enhance NO production through L·arginine supple mentation are equivocal at best. Although the L-arginine-NO pathway was the first to be discovered, it does not necessarily mean it is the primary pathway for the endogenous production of NO. In fact nitrogen cycling in bacteria and production of NO as an intermediate in denitrification may be one of the most primitive pathways known, dating back to the Archaean era. The now recognized human nitratenitrite-nitric oxide pathway that still relies on bacteria may be a redundant system for overcoming the body's inability to make NO from T .-arginine. It appears that we havt: at least two systems tor affecting NO production/homeostasis. The first is through the classical L-arginineNO pathway. This is a complex and complicated five-electron oxidation of L-arginine und if any of the co-factors become limiting, then NO production from NOS shuts down, and in many cases, NOS produces superoxide instead. The enzymatic production of NO normally proceeds very efficiently. However, in disease characterized by oxidative stress where e.ssential NOS cofactors become oxidized, NOS uncoupling, or conditions of hypoxia where oxygen is limiting, this process can no longer maintain NO production. This process is illustrated in Figure 2. ';'her~fore, one can argue saliently that there has to be an alternate route for NO production. It is highly unlikely that nature devised such a sophisticated mechanism of NO production as a sole source of a critical molecule. This alternate route involves the provision of nitrate and nitrite reductively recycled to NO (Figure 3). The two-electron reduction of nitrate to nitrite occurs through symbiosis with facultative anaerobic bacteria that reside in the crypts of our tongue. Nitrite reduction to NO can occur in a much simpler mechanism than nitrate. The 1-electron reduction of nitrite can occur by ferrous heme proteins (or any redox active metal) through the following reaction: N02 - + Fe(II) + H+ - NO+ Fe(III) + OH-. This is the same biologically active NO as that produced by NOS, with nitrite rather than Larginine as the precursor and is a relatively inefficient process. Much of the recent focus on nitrite physiology is due to its ability to be reduced to· NO during ischemic or hypoxic events. Nitri!e reductase activity in mammalian tissues has been linked to the· m,itochondrial electron transport system, protonation, deoxyhemoglobin, and xanthine oxidase. Therefore, for this reaction to occur, the tissues or biological compartment must have a sufficient pool of nitrite stored. Since plasma nitrite is a direct measure ofNOS activity, a compromised NOS system can also affect downstream nitrite production and metabolism, which can perhaps exacerbate any condition associated with decreased NO bioavailability. Considerable published data support the notion that exogenous nitrite contributes to whole body NO production: NO produced from nitrite in the upper intestine is up to 10,000 times the concentrations that occur in tissues from enzymatic synthesis, nitrite can act as a circulating NO donor, and nitrite can itself perform many actions previously attributable to NO without the intermediacy of NO. Experiments in primates revealed a beneficial effect of long-term application of nitrite on cerebral vasospasm. Moreover, inhalation of nitrite selectively dilates the pulmonary circulation under hypoxic conditions in vivo in sheep.Topical application of nitrite improves skin infections and ulcerations. Replenishing nitrate and nitrite through dietary means may then act as a protective measure to compensate for insufficient NOS activity under conditions of hypoxia or in a number of conditions characterized by NO insufficiency. Since a substantial portion of steady state nitrite 4 concentrations in blood and tissue are derived from dietary sources, modulation of nitrite and/or nitrate intake may provide a first line of defense for conditions associated with NO insufficiency. The recognition of this mammalian nitrogen cycle has led researchers to explore the role of dietary nitrate and nitrite in physiological processes that are known to be regulated by NO. Nitrite can transiently form nitrosothiols (RSNOs) under both normoxic and hypoxic conditions and a recent study by Bryan et a!. demonstrates that steady state concentrations of tissue nitrite and nitroso are affected by changes in dietary nitrite and nitrate (collectively, NOx) intake. Furthermore, enriching dietary intake of nitrite and nitrate translates into significantly less injury from heart attack. Previous studies demonstrated that nitrite therapy given intravt:nously prior to reperfusion protects against hepatic and myoc.ardial ischemia/repcrfusion (I/R) injury. Additionally, oral nitrite has also been shown to reverse L-NAME induced hypertension and serve as an alternate source of NO in viv9. These results have since been conobon.tlt:d in humans. ln tact, it has been reported that dietary nitrate reduces blood pressure in healthy volunteers. Commercial development of nitrite and nitrate enriched dietary supplements has been shown to impact important cardiovascular· risk factors in the aging population leading to a reduction in triglycerides and restoration of NO homeostasis. Furthermore, in the stomach, nitrite-derived NO seems to play an important role in host defense and in regulation of gastric mucosal integrity. However, this is pH dependent. Since stomach acid production declines with age and many patients are prescribed proton pump inhibitors, this pathway may be disrupted in the geriatric patient causing additional problems with maintaining NO horne.ostasis. Nitrite and nitrate therapy may then offer an all natural, over the counter and cost effective regimen for conditions associated with NO insufficiency. This has the potential to provide the basis for new preventive or therapeutic strategies and new dietary guidelines for optimal health. From a public health perspective, we may be able to make better recommendations on diet and dramatically affect the incidence and severity of cardiovascular disease and the subsequent clinical events. The major pathway for NO metabolism is the stepwise oxidation to nitrite and nitrate. For years, both nitrite (N02 ) and nitrate (N03 ) have been used as surrogate markers ofNO production in biological tissues, but there have not been any new developments in the use of NO biomarkers in the cliniGal setting for diagnostic or prognostic utility. In fact, NO status is still not part of the standard blood chemistry routinely used for diagnostic purposes. This is simply unacceptable given the critical nature of NO in many disease processes and new technologies should be developed. The only true measure of endothelial NO production (endothelial function) is through tlow mediated dilatation (FMD). FMD is a non-invasive ultrasound-based method where arterial diameter is measured in response to an increase in shear stress, which causes release ofNO from the endothelium and consequent endothelium dependent dilatation. FMD has been shown to conelate with invasive measures of endothelial function, as well as with the presence and severity of the major traditional vascular risk factors. Nitrite and nitrate have recently been shown to be biomarkers for cardiovascular and other diseases from both diagnostic and therapeutic aspects. However, it is not known if levels of NOx correlate with FMD. In addition to blood, urinary levels of NOx provide a means to assess systemic NO production in vivo, or renal handling of these anions which may be compromist:d in the geriatric patient. A report by Kleinbongard et a!. demonstrated that plasma nitrite levels in humans progressively decrease with increasing cardiovascular risk load. Risk factors included age, hypertension, smoking, and 5 hypercholesterolemia, conditions all known to reduce the bioavailability of NO. Although a correlation exists in the. plasma, it is not known whether the situation is mirrored in the heart or other tissue of interest in specific disease. The recent recognition of a human nitrogen cycle whereby nitrate and nitrite are reduced to NO by an enterosalivary circulation of nitrate now opens up the potential for using saliva as a potential biomarker for NO status in certain diseases. Aging and hypertension are well-documented cardiovascular risk factors. Most of the functional and structural vascular alterations that lead to cardiovascular complications are similar in aging and hypertension. Moreover, these vascular changes associated with essential hypertension are generally considered to be an accelerated form of the changes. seen with aging. When we are young and healthy, the endothelial production of NO through L-arginine is efficient and sufficient; however, as we age we lose our ability to synthesize endothelial1.lt:rived NO. Most of the works on the activity of NO in cells and tissues agree that the bioavailability or the generation of NOS derived NO decreases with aging. It has been proposed that superoxide can scavenge NO to form peroxynitrite and thereby reduce its effective concentrations in cells. It has ~1so been reported that there is decreased NOS expres~ion with aging both in constitutive and inducible isoforms .. Berkowitz etal.observed the upregulation of arginase (an enzyme that degrades· the natural substrate for NOS, L-arginine) in aged blood vessels and the corresponding modulation of NOS activity. Taddei et al. have shown that there is a gradual decline in endothelial function due to aging with greater than 50% loss in endothelial function in the oldest age group tested as measured by forearm blood flow assays. Egashiraet al. reported more dramatic findings in the coronary circulation of aging adults whereby there was a loss of 75% of endothelium-derived nitric oxide in 70-80 year old patients compared to young, healthy 20 year olds. Vita et al. demonstrated that increasing age was one predictor of abnormal endotheliumdependent vasodilation in atherosclerotic human epicardial coronary arteries. Gerhard et al. concluded from their 1996 study that age was the most significant predictor of endotheliumdependent vasodilator responses by multiple stepwise regression analysis. Collectively, these important findings illustrate that endothelium-dependent vasodilation in resistance vessels declines progressively with increasing age. This is illustrated in Figure 4. This abnormality is present in healthy adults who have no other cardiovascular risk factors, such as diabetes, hypertension, or hypercholesterolemia. Most of these studies found that impairment of endothelium-dependent vasodilation was clearly evident by the fourth decade. In contrast, endothelium-independent vasodilation does not change· significantly with aging, demonstrating that the responsiveness to NO does not change only the ability to generate it. These observations enable us to conclude that reduced availability of endothelium-derived NO occurs as we age, and to speculate that this abnormality may create an environment that is conducive to atherogenesis and other vascular disorders, including Alzheimers disease. It appears that aging interrupts NO signaling at every conceivable level, from production to inactivation. Given that NO is a necessary molecule for maintenance of health and prevention of disease, restoration of NO homeostasis may provide a new treatment modality for age and age related disease. Aging is considered the single largest risk factor related to cardiovascular related diseases and deaths. Cardia-protection decreases with increasing age and is attributed to a decline in NO. The lack of NO production can lead to hypertension, atherosclerosis, peripheral artery disease, heart failure, and thrombosis leading to heart attack and stroke, especially in geriatrics. Remarkably, 6 all of these conditions have been shown to be positively affected by dietary nitrite and nitrate interventions. Hypertension, along with aging is a well-known cardiovascular risk factor that leads to functional and structural alterations in the heart and vasculature. Vascular changes associated with hypertension, such as endothelial dysfunction, are an accelerated form of the type of changes seen with aging. Additionally, the presence of acetyl c.holine alongside a NO synthase i'lhibitot (L-NMMA) was tested for NO availability in the vasculature. A noteworthy finding is that after the age of 60 years old, the inhibiting effect of L-NMMA on response to acetylcholine was extremely weak, suggesting that N() availability· is completely l:umpromised in older populations. These results indicate that essential hypertension is characterized by an age-related reduction of endothelial function by mechanisms that ~'~pp.;-ar to be c;imilnr to tho~c observed hi older normotensive individuals. NO based therapies can reduce blood pressure. Transdermal nitroglycerin has been shown to reduce blood pressure in patients with recent stroke. Dietary intervention with nitrite and nitrate hn3 been ~huwu io modestly reduce blood pressure in humans showing remarkable efficacy using this approach. Atherosclerosis is the major source of morbidity and mortality in the· developed world. The magnitude of this problem is profound, as atherosclerosis claims more lives than all types of cancer combined and the economic costs are considerable. Reduced NO availability is a hallmark of atherosclerosis. The endothelium-derived NO plays a crucial role in regulating a wide spectrum of functions in the cardiovascular system, including vasorelaxation, inhibition of leukocyte-endothelial adhesion, vascular smooth muscle cell (SMC) migration and proliferation, as well as platelet aggregation. The concept of endothelial dysfunction arises from variations in blood flow observed in patients with atherosclerosis compared with healthy subjects. In healthy subjects, activation of eNOS causes vasodilation in both muscular conduit vessels and resistance arterioles. In contra~t, in subjects with atherosclerosis, similar stimulation yields attenuated vasodilation in peripheral vessels and causes paradoxical vasoconstriction in coronary arteries, thus indicating a decrease in the production and/or bioavailability of NO. Interestingly, endothelial dysfunction can be demonstrated in patients with risk factors for atherosclerosis in the absence of atherosclerosis itself. These observations lend credence to the concept that endothelial dysfunction is integral to the d·evelopment and progression of disease. Impaired endothelium may abnormally reduce vascular perfusion, produce factors that decrease plaque stability, and augment the thrombotic response to plaque rupture. There are a number of studies showing· that insufficient NO production from the endothelium is associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension,· smoking and severity of atherosclerosis, and importantly also has a profound predictive value for the future atherosclerotic disease progression. Augmentation ofNO or restoration of NOS function seems a logical means to inhibit atherosclerosis. Absence of eNOS in apoE-knockout mice accelerates atherosclerosis that is not caused by hypertension. Paradoxically, however, overexpression of endothelial NOS accelerates lesion formation in apoE-deficient mice demonstrating that enhanced NOS derived NO may not always be beneficial. Supplementation with tetrahydrobiopterin (BH4) reduced the lesion size to those seen in Apo E knockout mice revealing the requirement of enzyme cofactors. Even with BH4 supplementation there was still l'i.J effect on lesion development. These studies demonstrate the complexity of endothelium derived NO in the setting of atherosclerosis but clearly illustrate the dysfunctional eNOS/NO 7 path~'.'ay as an early marker or a common mechanism for various cardiovascular disorders and therefore provides an ideal target for therapeutic or preventive intervention including alternative NOS independent sources of NO. Stokes et al. have demonstrated that supplementing nitrite in the drinking water inhibits the adhesion and emigration of leukocytes to the vascular endothelium, one of the earliest events of atherogenesis suggesting this nitrate-nitrite-NO pathway may be useful in preventing chronic vascular disease. Thrombosis affects nearly 1 million patients in the United States annually. Out of those million, nearly 300,000 are reported as thrombosis related deaths. -\ majority of current treatment options are centered on preventative anticoagulants, such as warfarin but with risk of bleeding. NO inhibits platelet activation, adhesion, and aggregation by influencing several signaling pathways, including activation of sGC anci . incr~;>asing intraoollular cGMP, iuhlbitlon of phosphatidylinositol~3 kinase; and inhibition of capacitativecation influx and agonist-dependent increases in intracellular calcium. These molecular events lead to an impairment of platelet activation, adhesion, secretion, fibrinogen-binding to glycoprotein lib/lila, and ultimately, aggregation. In addition, NO promotes platelet disaggregation. In conjunction with its vasorelaxing actions, these anti-platelet effects of NO maintain blood fluidity and tissue perfusion. A constitutive NO synthase has been found in both human platelets and megakaryocytic cells and this isoform is active. Using ·an NO-selective microelectrode adapted to a platdet aggregometer, Free,dman et al. recently showed that this platelet-derived NO not only modestly modulates platelet activation to strong and weak agonists but, more importantly, markedly inhibits platelet recruitment to the growing platelet thrombus. NO, derived both from the endothelial cell and the platelet, modulates platelet activation, adhesion, and aggregate formation, thereby serving as an important deterrent to platelet-mediated arterial thrombosis. NO insufficiency, either through reduced production or oxidative inactivation leads to thrombotic events.Efforts to restore the normal vascular redox balance and/or to restore normal NO availability may provide one therapeutic avenue for reducing platelet-dependent arterial thrombosis in older patients. In fact, recent studies have shown that dietary nitrate can inhibit platelet aggregation again demonstrating this dietary approach to replete NO may provide first line of defense for NO insufficiency. The most feared disease of the geriatric population is Alzheimer's disease (AD). In the United States, around 5.4 million people live with AD, a type of dementia. Patients with AD lose brain function, resulting in problems with language, perception ·and memory. AD can start before age 60 (early onset) or after age 60 (late onset). The risk for AD increases as a person ages and that rising risk is being seen as the baby boomers start turning 65 years old. Out of every eight baby boomers; one will get AD after she turns 65 years old; at age 85, that risk grows to one in two. With the 65 and over population in the United States expected to double by 2030, there may be up to 16 million people with AD by 2050; there may be almost one million new AD cases diagnosed each year. Each year in the United States, more than 800,000 people die from this neurological disease. It is the sixth leading cause of death, with the number of deaths rising 66 percent from 2000 to 2008. There is becoming a clear and convincing association with AD and NO. Decreased levels of NOx has been detected in patients with different forms of dementia especially AD. The exact etiology of sporadic AD is unclear, but it is interesting that cardiovascular risk factors including 8 hypertension, hypercholesterolemia, diabetes mellitus, aging, and sedentary lifestyle are associated with higher incidence of AD. Th~ link between cardiovascular risk factors and AD has yet to be identified; however, a common feature is endothelial dysfunction, specifically, decreased bioavailability of NO. The pathogenesis of Alzheimer's disease is closely associated with the accumulation of amyloid-~ (A~) peptides, which eventually form neuronal deposits known as senile plaques on the outside surface of the neurons and lead to neuron death. AD is characterized by progressive loss of neurons, cognitive decline, and two Jdining histopathologies: extracellular amyloid plaques and intracellular tangles composed primarily of AP peptide and hyperphosphorylated tau, respectively. Furthermore, AD is often accompanied by cerebrovascular dysfunction, as well as amyloid deposition within the cerebral vessels, termed cerebral amyloid angiopathy. NO in the brain can be produced either by iNOS in microglia and astrocytes, or by constitutive NOS in neurons and endothelial cc.::lls (nNOS and eNOS). A large body of evidence suggests that the NO produced by neuronal and endothelial constitutive NOS is responsible for neuroprotection during AP-induced cell death, while NO production in the case of iNOS activation plays a neurotoxic role due to the inflammatory response caused by the over generation of other reactive nitrogen species from NO.A decrease in nNOS and an increase in hippocampal iNOS have been demons trated in aged rats, suggesting the dual roles and complexity of NO signaling in the brain and during AD. In mice, higher levels of constitutive NO 1-'roduced by NOS protects beta-amyloid transgenic mice from developing most typical human symptoms of AD.The protective role of NO in AD pathogenesis has been linked to NO/sOC/cOMP/Protein Kinase 0 (PKO) signaling cascades. Treatment with NO donors and cOMP analogues suppresses cell death, and increasing intracellular ·cOMP levels prevents inflammatory responses in brain cells. Moreover, the use ofthe NO donors, sOC stimulators, and cOMP-analogs reverses learning and memory impairment through PKO activation, in part by reestablishing the enhancement of the transcription factor cAMP-responsive element binding protein (CREB), which is phosphorylated during long term potentiation. It has also been shown that NO modulates expression and processing of amyloid beta precursor protein. However, an accumulation of AP inhibits the NO signaling pathway and therefore may suppress the protective effects of endogenous NO in the brain. Chronic administration of fibrillar AP c;ecroses the expression of sOC in cultured rat astrocytes, desensitizing them to treatment with sodium nitroprusside. Acute AP administration blocks NO-induced vasoactivity in rats [and inhibits NO-stimulated phosphorylation of CREB. In postmortem temporal cortex from a series of AD patients there was reduced NO responsive sOC providing the first evidence for a loss of NO responsive sOC activity in AD brain. Alternatively, current research suggests S-nitroslyl~tion, may be responsible for cOMP independent mechanisms of NO and can contribute to neurotoxicity in neurogenerative diseases such as AD. Consequently, NO does not always protect against disease and may help facilitate neurode generative disorders through nitrosative stress and dysregulation of production. A common theme in many neurodegenerative disorders is the finding of abnormal aggregates of misfolded proteins. Recent findings have implied that NO-related species may significantly prtir.ipate in the process of protein misfolding through protein S-nitrosylation under degenerative conditions. Qu et al. demonstrate that Cdk5 activity, a cyclin dependent kinase responsible for neuronal functions, is regulated by S-nitroslylation. They found significantly increased S-nitrosylated Cdk5 (SNO-Cdk5) levels in postmortem human brain tissues of patients 9 with AD compared to control brain tissue. Significantly, SNO-Cdk5 was not detectable in control human brains, thus indicating that measurable levels of SNO-Cdk5 are representative of a diseased state. Additionally, researchers reported that formation of SNO-Cdk5 contributes to NMDA-induced spine loss, neuronal damage, and to AP-induced loss of synaptic spines. In conclusion, the SNO-Cdk5 mediated pathway may contribute to the path agenesis of AD and serve as a unique therapeutic for restoring spine damage in AD and other neurodegenerative diseases. · Collectively, the literature demonstrates a critical role for NO in the development of AD. It appears that normal and sufficient NO production/availability can modulate and inhibit the expression and formation of AP but once AP becomes present it further compromises NO activity. This crel'ltes a perpetual system ofNO insufficiency and a feed furwurd mechanism that may accelerate AD progression. The NO pathway (both cGMP and through S-nitrosylation) may be an important therapeutic target in preventing and treating mild cognitive impairment, as well as AD. In fact, a high nitrate diet has been shown to increase regional cerebral blood flow to the frontal lobe in older patients. · It appears that the inability to produce sufficient NO under the right preclinical conditions enhances the risk for a number of diseases that plague the older population. If true, then there exist an opportunity to intervene early during this process, implement strategies to restore NO homeostasis, and, perhaps, delay or prevent the onset and progression of certain diseases. This gradual loss ofNO activity with age can be sped up or slowed down based on individual lifestyle and diet. Adopting healthy habits such as a good diet and exercise can prolong the precipitous ·•· drop :n NO production with age. To the contrary a poor diet along with physical inactivity can accelerate the process and lead to a faster decline in NO production at a younger age. Therapeutic strategies directed at improving endothelial function or providing an alternative source of NO should be the primary focus because they may reduce the incidence of atherosclerosis or other diseases that occur with aging, even perhaps AD. The role of diet in the prevention and control of morbidity and premature mortality due to noncommunicable diseases has been well established by vast population-based epidemio logical studies carried out during the last decade. NO is essential for maintaining normal blood pressure, preventing adhesion· of blood cells to the endothelium, and preventing platelet aggr_egation; it may, therefore, be argued that this single abnormality, the inability to generate NO, puts us at risk for diseases that plague us later in life, such as atherosclerosis, myocardial infarction, stroke, end neripheral vascular disease. Are dietary and nutritional strategies utilizing nitrite and/or nitrate to restore NO homeostasis the best approach? More clinical trials are needed to define the context for risks vs. benefit. Although modestly increased associations between consumption of foods containing nitrite and nitrate and certain cancers .have been reported in some prospective epidemiologic studies, findings across studies have been largely inconsistent and equivocal and thus the overall burden of proof remains inconclusive. As with any therapy or treatment regimen, a risk benefit evaluation should be considered and understood for certain persons or patient populations. However, given the emerging data on the growing number of benefits from diets and foods enriched in nitrite and nitrate, we predict the benefits will far outweigh any risks. What remains clear is developing strategies and new technologies designed to restore NO availability is essential for inhibiting the progression of certain common chronic diseases. 10 NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS). These enzymes convert L ·- arginine into L -citrulline, producing NO in the process. Oxygen and different co factors such as FAD, FMN, heme and tetrahydrobiopterine are necessary which influence NO synthesis by this rection. The dysfunctional nitric oxide synthase (NOS) nitric oxide pathway is considered an early marker for various cardiovascular disorders. Decreased bioavailability of endothelial nitric oxide plays a crucial role in the development and progre~sion of a number of human diseases. Endothelial dysfunction results from decreased nitric oxide production or increased degradation of nitric· oxide. ln certain aspects endothelial dysfunction-can be defined as the inability to -generate NO. Endothelial dysfunction is a physiological dysfunction of normal biochemical processes carried out by the-encinth~liutl1, the eells that line tho inner gurface ufall uluuU vessels including arteries and veins (as well as the innermost lining of the heart and lymphatics). Endothelial dysfunction is associated with several cardiovascular disorders, including atherosclerosis. l'rior attempts to restore nitric oxide homeostasis have m~t significant challenges. L-arginine and antioxidant supplements have consistently failed in clinical trials. It is known that NOS enzymes produce nitric oxide by catalyzing a five electron oxidation of the guanidino nitrogen of Larginine. While nitric oxide is produced through oxidation of the semi-essential amino acid Larginine by NOS, the L-arginine-nitric oxide pathway is dysfunctional in patients with endothelial dysfunction. Thus, feeding the nitric oxide pathway through L-arginine supplementation is potentially both ineffective and detrimental through the production of superoxide instead of nitric oxide. Prior attempts to enhance nitric oxide production with organic nitrates such as nitroglycerin have faced challenges. Early entry therapy with organic nitrates do not significantly improve survival in myocardial infarction but increases the beneficial effects of the Angiotensin Converting I:nzyme (ACE)-inhibitor enalapril by 50%. Certain short-term experimental and clinical investigations suggest that nitrate . tolerance induced by nitroglycerin is ~ssociated with toxic effects in the vasculature. Chronic and long-term organic nitrate therapy has been associated with reduced survival when used in patients with coronary artery disease. Endothelial dysfunction induced by a continuous treatment with nitroglycerin may be an additional risk for patients who receive continuous nitroglycerin to treat .conditions such as unstable angina and acute heart failure. . · Previous studies have shown that nitrites widen blood vessels, but US researchers writing in Nitric Oxide: Biology and Chemistry, the peer-reviewed journal of the Nitric Oxide Society, say theirs was the first to find that nitrites also increase blood flow to the brain. Beetroot contains high concentrations of nitrates, which are converted into nitrites by bacteria in the mouth. Nitrites help open blood vessels in the body, increasing blood flow and oxygen to places lacking in oxygen.Beetroot is a dark red vegetable with an acquired taste which has been getting a lot of coverage in the news. It has been linked with better stamina, improved blood flood and lower blood pressure 11 , Most beetroot is round and red, but yellow, white and stripy versions are available.The beetroot taste is described as sweet, earthy and tender to eat. It is grown in the ground and is related to turnips, swedes· and sugar beet. It contains potassium, magnesium, iron, vitamins A, B6 and C, folic acid, carbohydrates, protein, antioxidants and soluble fiber. Researchers have known for some time that juice may help lower blood pressure, but in 2010 UK researchers revealed that nitrate is the special ingredient in beetroot which lowers blood pressure and may help to fight heart disease. In a Queen Mary University of London study, healthy participants had-to drink a glass··of --·beetroot juice while others had a dummy (placebo) drink. Others took nitrate tablets.Blood pressure was lowered within 24 hours in people who took nitrate tablets and those who drank. beetrootjuice.The researchers admitted to BootsWebMD that beetroot juice is a love it or hate it kind of drink, but found people in the study didn't mind it so much when they were drinking it every day.People with very high blood pressure can end up being on multiple tablets, so a more natural approach could prove popular if the initial research results are confirmed.The study was funded by the British Heart Foundation and is . published online in the American Heart Association journal Hypertension. Drinking beetroot juice increases blood flow to the brain in older people, which may be able to . fight !he progression of dementia, a 2010 study suggested.Beetroot contains high concentrations of nitrates, which are converted into nitrites by bacteria in the mouth. Nitrites help open blood vessels in the body, increasing blood flow and oxygen to places lacking in oxygen. There are some interesting side effects of eating too much beetroot. It can turn urine pink, which can be mistaken for blood in the urine. · If you get kidney stones because of too much calcium, you may be advised to cut down on oxalates in your diet. Beetroot is just one food which contains oxalates, which prevent calcium from being absorbed by your body allowing it to build up as stones in the kidney. The British Dietetic Association says beetroot contains flavonoids called anthocyanins which are responsible for the deep pigments. Anthocyanins, the BDA says, can help with recovery from the stress of exercise during training and competition as well as helping to couriter the effects of pollution on the. body. Hawthorn is a plant. The leaves, berries, and flowers of hawthorn are used to make medicine.Hawthom is used for diseases of the heart and blood vessels such as congestive heart failure (CHF), chest pain, and irregular heartbeat. It is also used to treat both low blood pressure and high blood pressure, "hardening of the arteries" (atherosclerosis), and high cholesterol. So far, research suggests that hawthorn might be effective in treating congestive heart failure, but there hasn't been enough research on other heart-related. uses to know if it is effective for them. Research suggests that hawthorn· can lower cholesterol, low density lipoprotein (LDL, or "bad chole~terol"), and triglycerides (fats in the blood). It seems to lower accumulation of fats in the liver and the aorta (the largest artery in the body, located near the heart). Hawthorn fruit extract 12 may lower cholesterol by increasing the excretion of bile, reducing the formation of cholesterol, and enhancing the receptors for LDLs. lt also seems to have antioxidant activity. L-citrulline is a naturally occurring amino acid found in food, such as watermelons, and also made in the body. Our bodies change L-citrulline into another amino acid called L-arginine and also to nitric oxide. L-citrulline might help increase the supply of ingredients the body needs to making certain proteins. It might also help open up veins and arteries to improve bluud flow and reduce blood pressure. Vitamin Bl2, or cobalamin, is essential to a wide variety of critical body functions. We need B12 for nervous system health, cardiovascular health, energy production and longevity. Getting optimal amounts ofthis important nutrient can do great things for our· minds and bodies, but unfortunately, many people aren't even getting the bare minimum.Vitamiil B12 is an essential nutrient for the human body. In its active form, it is a methyl group donor that is involved in energy production, homocysteine metabolism, nerve function and neurotransmitter production. B12 works with folate to create red blood cells and the protective coating around nerve cells, to convert food to energy and to synthesize and repair DNA. · B12 deficiency is not a symptom experienced only by the sick, malnourished and elderly. On the contrary, it affects millions of Americans,_ even those with healthy diets and lifestyles. A recent study conducted by Tufts University suggests that B12 deficiency and insufficiency affect 64% of people between the ages of 26 and 83, and that suboprimal levels are equally as common at every age. Clinical deficiency (serum levels below 148 pmoi/L) affected 9%, or nearly one in ten people, out of 2,999 subjects. These dangerously low levels are known to cause nerve damage, cognitive decline, loss of memory, fatigue, and anemia, among other things. An additional 16% of subjects were verging on deficient (levels below 185 pmoi/L), and 39% had levels in the lownormal range (below 258 pmoi/L). According to a recent study published in the September 2008 issue of Neurology, B 12 levels below 308pmoi/L are associated with an increased risk of brain shrinkage and cognitive decline. Together, these two studies suggest that 56% of the population may experience neurological impairment as a result of low levels of B 12, without being diagnosed as B 12 deficient. One of vitamin B 12's many vital functions is the formation and maintenance of the outer layer of nerves, called the myelin sheath. The myelin sheath is the fatty insulation around nerve cells that protects neurons and allows them to properly conduct signals. Integrity of the myelin sheath is essential for healthy brain function and is dependent upon methylation reactions that require B12. B12 also ·influences the production of neurotransmitters that control memory, thinking, motor function and moods. B 12 deficiency affects the nervous system first, by damaging the myelin sheath and then the entire nerve cell. This damage can result in a host of neurological conditions including multiple sclerosis, neuropathy, impaired coordination. and loss of vision, hearing and memory. Animal studies have revealed that the methyl form of vitamin B12 (methylcobalamin) promotes the regeneration of nerve cells. Limited human trials suggest a role for B 12 in slowing the progression of neurodegenerative disease and lessening pain associated with neuropathy. 13 B12 deficiency can also result in elevated blood levels of the amino acid metabolite homocysteine. Numerous studies have cited a correlation between elevated homocysteine and Alzheimer's, dementia, depression and overall cognitive decline. Vitamin B 12 is needed to create red blood cells and to convert homocysteine to methionine. Both of these functions are critical to the health 'of the cardiovascular system. Deficiencies of B 12 can result in megaloblastic anemia, characterized by oversized, immature red blood cells, and buildup of homocysteine in the blood, a risk-factor for heart disease. B12 is essential for energy production in every cell ofthe body and has earned the nickname "the energy vitamin." Supplying our bodies with adequate amounts of B12 helps our cells derive energy from the proteins. fats and c::~rhohydrates we eat. B 12' s role in mclauulisrn Impacts the function of every tissue in the body, including the musdes, the heart and the brain. Vitamin D12 is essential for the synthesis and repair of DNA and it supports healthy gene expression. Gene expression is the process by which our genetic material is used to generate biochemicals within the body, and it influences whether we will live long, healthy lives or will suffer from disease. Nutrients that affect gene expression have the ability to "tum on" genes that promote health while "turning off' those that undermine health. Though B 12 does not directly regulate gene expression, it plays an important role in the production and recycling of S-adenosyl methionine (SAMe), a biochemical that reacts with DNA to turn genes on or off. This reaction, called methylation, is a natural reaction within our bodies that supports healthy gene expression. Therefore, supplementing with B 12 supports the healthy replication and function of our genetic material. Vitamin B 12 is a product of bacterial fermentation and is found exclusively in animal products. Beef, poultry, fish, cheese and eggs are all good sources of B 12. Although an inactive analogue of vitamin B12 is found in some plants like algae, this form is not used by our bodies. Absorption of B12 in the small intestine requires the help of a glycoprotein known as intrinsic factor. Intrinsic factor, secreted by the parietal cells in the stomach, has a low affinity for inactive B12 l:lnalogues found in plant foods. Ifthese inactive analogues are absorbed into the body, they are taken to the liver and then excreted in the feces and urine. The following categories, would likely to be benefited from supplementation: ~ A senior - an estimated 40% of seniors have low stomach aciditY (atrophic gastritis), which is linked to impaired absorption of protein-bound vitamin Bl2, found in food. The unbound B 12 found in supplements is generally better absorbed. ~ A vegetarian or vegan - vegetarians often do not consume adequate food sources of B 12 and vegans do not consume any food sources ofB12 (plant sources are analogues and are not absorbed); studies have shown that up to 50% of vegetarians and 80% of vegans are deficient. ~ A pregnant- pregnancy increases the demand for B12 to create more blood cells and to nourish the baby's growing nervous system; B12 deficiency during pregnancy has been linked with neural tube defects. 14 y .. ' ~ A man with low sperm count or low motility - B12 supports healthy sperm cell replication. When given to men without B12 deficiency, it has reportedly increased sperm count and motility. ~ An acid blocker- Use of proton pump inhibitors has been linked with B 12 depletion. ~ A person taking metformin - research has shown a correlation between metformin & B 12 deficiency. As dosage and duration increased, so did risk ofB12 deficiency. ~ A person havingGI problems (H, pylori, stomach acid imbalances, Crohn's Disease, Gastric or Duodenal Ulcers, etc.)- these complications interfere with absorption; studies have found low B 12 levels in individuals with stomach and/or intestinal problems. ~ A postmenopausal woman: Bone health is a concern for all of us, but particularly for postmenopausal women, who are most likely to suffer from bone loss and osteoporosis. B12 plays ~n important role in bone health via its rok in homocysteine metabolism. Women with homocysteine levels above 15 IJ.mol/L were found to have a 96% higher risk of low bone density than women with levels·below 91J.moi/L. ~ To improve memory, mental clarity, mood or energy levels- B12 supports all of these bodily functions. Cyanocobalamin and methylcobalamin are the two most common chemical forms of B12. Cyanocobalamin is B12 (cobalamin) bound to a cyanide molecule while methylcobalamin is B12 bound to a methyl group. Both forms are produced synthetically. Methylcobalamin is considered an active form because it does not need to be converted in the body before it can function as B12. Cyanocobalamin is not an active form because it must be converted to methylcobalamin before it c:1n function as B12. Another form of B12, called dibencozide (also known as adenosylcobalamin),·is another active form ofB 12. B 12 comes in sublingual, pill and liquid form. Sublingual form (a tablet that dissolves under the tongue) is a popular method of oral administration because the B12 is absorbed directly into the bloodstream through the mouth, and does not require intrinsic factor. This may be beneficial for individuals with impaired digestion or inadequate intrinsic factor. Although many medical doctors give B12 injections, oral administration is equally as effective, even in the absence of intrinsic factor. Research has established that, in individuals with pernicious anemia (B12 deficiency symptom), the average absorption rate of cyanocobalamin is 1.2 percent for a wide range of doses. This means that the average person taking a daily dose of 2.50 icrograms would absorb 3 micrograms. Since the daily turnover rate of B12 is about 2 micrograms, 250 meg daily would be sufficient for many people. However, there is little risk in taking higher doses, up to 2,000 micrograms daily, and many people benefit greatly from amounts as high as 5,000 micrograms per day or higher. Higher doses are generally more effective at replenishing diminished B12 stores rapidly. Several medical tests are available to assess the levels ofB12. These include: Serum Bl21evels-the most common, but often inadequate test. ~ Holotranscobalamin II--can detect B12 deficiency in its earliest stages-low levels indicate that the B 12 stores are diminishing. ~ Serum levels or Urinary excretion of methylmalonic acid-elevated levels indicate that cellular insufficiency or deficiency has already manifested. 15 y ~ Serum levels of homocysteine-elevated levels indicate that cellular insufficiency or deficiency has already manifested. Limitations oftesting: Serum Bl2 levels alone are inadequate to diagnose B12 deficiency and insufficiency. In the original Framingham Study, more than half of seniors with cellular B12 deficiency had serum B12levels considered normal. This finding can be attributed to 2 factors: 1. The clinical ranges for "normal" serum B 12 in the United Slates are much too broad. While levels between 200 pmol/L and 300 pmol/L are considered normal in the U.S., individuals with levels this low often have obvious B 12 deficiency symptoms. In Japan and some European countries, the clinical cutoff for deficiency is betwet:n 370 and 407 pmol/L 2. A serum B12 test measures all circulating B12, but about 80% of this B12 is unavailable to most cells. A holotranscobalamin II test, on the olht:r hand, measures the remaining 20% of circulating cobalamin that is attached to a carrier molecule, enabling it to reach the body's cells. Levels ofholotranscobalamin can be low in individuals with normal serum B12-a situation that results in cellular deficiency. Methylmalonic acid and homocysteine are also indicators of cellu;ar deficiency. These three functional metabolite· tests are very important for accurately assessing B 12 levels in the body. · The NHLBI Study: The Promise of New Medical Uses for Sodium Nitrite for Heart Attack and Organ Damage suggest that: Sodium nitrite, a naturally occurring chemical and common meat preservative, is only used medically to treat cyanide poisoning. But if the results of a new animal study hold up under further research in people, the chemical may one day be used to protect and preserve tissue and organ function after heart attack, high risk abdominal surgery, and organ transplantation. The new study was conducted by scientists with the National Heart, Lung, and Blood Institute (NHLBI) ofthe National Institutes ofHealth (NIH) in collaboration with investigators supported by the National Institute of Diabetes and Digestive and Kidney Diseases at Louisiana State Univ<>:rsity Health Sciences Center and published in The Journal of Clinical Investigation. The scientists found that low concentrations ·of sodium nitrite had a strong protective effectpreventing cell death in the hearts and livers of mice undergoing experimental heart attack and liver injury. In the heart study, nitrite reduced the size. of the area of dead tissue known as an infarct by 67 percent compared to control animals given nitrate, another nitrogen compound. This potent protective effect was observed at concentrations of nitrite in blood that were only slightly higher than the physiological normal levels in blood. The study, Jed by David Lefer, Ph.D., of Louisiana State University Health Sciences Center in Shreveport and Mark Gladwin, M.D., Head of the Vascular Therapeutics Section of the NHLBI's Cardiovascular Branch, follows another study conducted by the NIH research team that found that infusions of sodium nitrite into the human circulation leads to the production of nitric oxide (NO), a strong blood vessel dilating molecule that increases blood flow. The conversion of nitrite .to NO will occur only in tissue or blood that is very low in oxygen. It was this finding that triggered the team's interest in sodium nitrite as a treatment/preventive for the tissue damage and cell death that can occur in conjunction with organ transplantation, heart attack, and treatment of a heart attack. 16 In both the liver and heart components of the current study, the research team compared the effects of both lower and higher concentrations of nitrite versus control' treatments of saline or nitrate, a chemical compound that is related to nitrite but cannot convert to NO. in the blood. Surprisingly, they found that only low concentrations of nitrite provided protection against injury. The investigators are currently studying the mechanism for the protective effect of sodium nitrite r.nd they believe it is related in some way to the conversion of nitrite to nitric oxide. "The remarkable thing about nitrite is that it is only converted to nitric oxide in the organs and· tissues with the .lowest oxygen levels, allowing for targeted NO delivery - and thus improved blood flow - to tis.•me~ under gtrecs. Moro re3cnrch is neeucu lu look at the effectiveness of nitrite in various organs and disease states in humans," said NHLBI's Gladwin who is also an investigator in the Critical Care Medicine Department, NIH Clinical Center. Gladwin is currently studying the use of sodium nitrite as a way to help adults with sickle cell disease. It is hoped that this treatment will reverse the effect of decreased blood flow due to the patients'. "sickled" blood cells. Patients with sickle cell disease have abnormal hemoglobin molecules in their red blood cells. The molecules damage the red cells, causing them to change into a crescent or sickle shape and stick to blood vessel walls. This can lead to· narrowed, or blocked, blood vessels leading to pain, damage, and anemia. Further studies either underway or in planning translate the new findings to humans. These studies evaluate sodium nitrite's effect on heart attacks, kidney failure, solid organ transplantation, cerebral vasospasm (a complication of a ruptured aneurysm leading to reduced blood flow and possible stroke), and high blood pressure in the lungs in babies. One nutrient that can positively affect nitric oxide synthesis is vitamin C, or ascorbic acid. A study published in 2003 in "Circulation Research" found that vitamin C increased the activity of the enzyme nitric oxide synthase, the protein that produces nitric oxide. The vitamin may support nitric oxide production and help to maintain the levels of the compound within your body. Attempts targeting delivery of nitric oxide to precise cellular locations have also faced challenges. The most widely known and effective means for targeted delivery to the pulmonary circulation is inhaled nitric oxide, which requires specialized inhaling equipment. Biomaterials for sustained release of nitric oxide for topical applications for wound healing, infections, etc. are still in development. Nanoparticle delivery of nitric oxide is still emerging, particularly in cancer biology. NO-eluting stents or nitric oxide-coating of orthopedic implants for preventing biofilm growth and infection is also still in development. Phosphodiesterase inhibitors, such as sildenafil, do not directly affect nitric oxide production but act through affecting the downstream second messenger of nitric oxide, cyclic guanosine monophosphate ( cGMP). Oral Formulation Concerns an oral disintegrating tablet (ODT) is a solid oral dosage form that disint~::grates and dissolves in the mouth without water within 1 minute or less. In the literature, ODT:; also are identified as rapidly-dissolving tablets, orally disintegrating, quick-dissolve, orodisperse, mouth-dissolving, fast-melt, and rapid-disintegrating tablets. ODTs were designed 17 ,Y tor C:-iildren and the elderly or for any individual that has difficulty with swallowing, especially entire tablets or capsules, commonly referred as dysphagia. With an ODT tablet, all of the components will liquefy in the mouth and then the individual swallows the liquid. However, there are a number of disadvantages and complexities associated with the formulation development and scale-up process of ODTs, including drug loading, taste masking,friability, high facility and manufacturing costs, and stability of the finished product.Poor friability is the most frequent problem found in ODTs. For a compressible tablet to dissolveinstantly, it may be quite friable. However, making the tablet harder and less friable maynegatively impact the fast disintegration and dissolution time. Generally, an ideal ODT musthave a balance between durability, friability and speed of disintegration/dissolution. Accordingly, there exists a large unmet need to recapitulate nitric oxide homestatis in the body using an effective delivery system. Oral disintegrating tablets were previously consideredunsuitable because they dissolve in the mouth, where oral dispersion of nitric oxide wasperceived as ineffective. Oral disintegrating tablets are designed for children, the elderly andindividuals with difficulty swallowing. Complexities challenge the formulation, developmentand scale-up process of oral disintegrating tablets, including drug loading, taste masking,friability, high facility and manufacturing costs~ and stability of~he finished product. Regular tablets and capsule do not allow the proper reaction to take place and minimize nitricoxide generation. Capsules pass through the gastrointestinal tract and release their contents in thestomach. However, many people taking proton pump inhibitors or who may have achlorhydriafor other reasons may not experience the same benefit since low pH in the stomach i~ required togenerate NO from nitrite. Nitrosative chemistry occurring in the stomach also has the potential toform potentially carcinogenic N-nitrosamines. By slowly titrating the saliva one can avoid theburst ofnitrosative chemistry that would occur at once in the stomach. SUMMARY OF THE INVENTION The present invention solves the above mentioned problems, restores the nitric oxide homeostasis in an endothelium-independent manner through a safe and effective oral delivery system. The present invention restores physiological levels of nitric oxide in the body thereby treating or preventing disease. The present invention overcomes the challenges faced in the prior art by delivering bioactive nitric oxide sources to targeted locations, including the mouth where such sources may be reacted to produce nitric oxide which is absorbed in the mouth and then circulated in the body. The nutraceutical tablet is meant to increase or restore Nitric oxide level in the body. This is natural way to increase nitric oxide in the body. Nitric oxide is an important signaiing molecule, which is required for healthy blood circulation. A nutraceutical composition comprising of Vitamin C, Hawthorn Berry, Beetroot, L- Citruline, Sodium Nitrite, Methylcobalamin and CO Q 10 in an oral disintegrating tablet form. BRIEF DESCRIPTION OF THE DRAWINGS An embodiment of the present invention is described in greater detail below and more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawi~gs: 18 FIGURE 1 shows NO as one of the most important signaling molecules in the body, and its involvement in every organ system where it is responsible for modulating an astonishingvariety of effects. FIGURE 2 shows the classical L-arginine-NO pathway. It explains the NO production and biochemistry. There are a number of critical steps for the NOS production of NO from Larginine. Under healthy conditions (top), enzymatic function proceeds normally. FIGURE 3 shows the two pathways for endogenous nitric oxide (NO) production. The Larginine NO pathway can be enhanced through regular exercise, which becomes dysfunctional with age. The dietary pathway through reduction of nitrate and nitrite is not affected by age. FIGURE 4 shows the graphical representation of NO production in percentage in the body of different age groups. It explains the consequences of NO insufficiency in the aging population and also a comparison within population of different dietary and exercise habits. FIGURE 5 shows the process flow diagram of different stages involving raw materials and equipments in manufacturing ofthe nutraceutical composition. DETAILED DESCRIPTION OF THE INVENTION Definitions 'i he term "Nutraceutical" refers to products that range from isolated nutrients, dietary supplements and herbal products, specific diets and processed foods such as cereals, soups, and beverages. Neuraceutical is regarded as the bio active sqbstance and the constituents are either of known therapeutic activity or are chemically defined substance generally accepted to contribute substanWtlly to the therapeutic activity ofthe drug. The present invention is explained in detail below. This description is not intended to be a detailed catalogue of all the different ways in which the invention may be implemented, or all features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. ,, Genr~, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof. It is becoming increasingly clear that many diseases are characterized or associated with perturbations in nitric oxide (NO) production/signaling. Therapeutics or strategies designed to restore normal NO homeostasis will likely have broad application and utility in human health. The production of nitric oxide is one of the most important biological processes in the body. Despite NO's known and accepted importance in human physiology, there have been no hallmark therapeutic breakthroughs or effective strategies developed to· enhance or restore NO homeostasis in humans at risk for cardiovascular disease. Providing a rich source of nitrate either through direct supplementation with nitrate salts or through nitrate rich foods such as beet root, for example, will increase . circulating levels of nitrite. However, because of the inherent inefficiencies that exist for reducing nitrite to NO along the physiological oxygen gradient, this step in the pathway must be enhanced to effectively utilize nitrite to make NO. · 19 The nutraceutical composition includes a novel daily regimen that can safely and effectively restore nitric oxide levels as well as reduce blood biomarkers routinely used to assess patient risks for developing cardiovascular disease. The nutraceutical composition is distinct from nitri~ oxide production through endothelial production using the L-arginine pathway. The nutraceutical composition utilizes dietary sources of nitrite~ nitrate, anti- oxidants and vitamins. The present nutraceutical composition comprising a nitrite salt preferably sodium nitrite wherein ,r:itrate source is preferahly Reet root extract, amino source preferably L-citrulline, vitamins preferably, Vitamins C along with sweetening agents, antioxidants, disintegrants, lubricants, col9rs andflavors. The nutraceutical composition further comprising CoQ 10 wherein CoQlO stands for Coenzyme QlO which is an oil-~oluble, vitamin-like substance and its primary function in cells is generating energy. As botanical source is generally acceptable and regarrled safe for both human and animal consumption, the botanical source for nitrite_ reduction used here in the invention is Hawthorn berry extract. EXAMPLES The following examples are included to demonstrate preferred embodiments ofthe inventions. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the inventions, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the inventions. EXEMPLARY FORMULATIONS EXAMPLE 1 (A): In an exemplary embodiment, the formulation of nutraceutical composition is shown below: r-_ S.No. Ingredients 1 Vitamin C 2 Mecobalamin 40% Overages 3 Beet root extract 4 Sodium Nitrite 5 L-Citrulline 6 Hawthorn Berry 7 CoQ 10 8 Pearlitol 9 Xylitol 10 Pharmatose DCL-15 II Citric acid anhydrous 20 r 12 Sucra1ose 13 Mixed Fruit (flavour) 14 Pineapple (flavour) 15 Banana (flavour) 16 Vanilla (flavour) 17 Croscarmellose sodium 18 Erythrosine lake 19 Aerosit· 20 Talc --- 21 Magnesium stearate EXAMPLE l(B): In an exemplary embodiment, the formulation of nutraceutical composition is shown below: S.No. Ingredients ~ Vitamin C 2 Mecobalamin 40% Overages 3 Beet root extract 4 Sodium Nitrite 5 L-Citrulline 6 Hawthorn Berry 7 CoQ 10 8 Pearlitol 9 Xylitol t-- 10 Pharmatose DCL-15 11 Citric acid anhydrous 12 Sucralose 13 Mixed Fruit (flavour) 14 Pineapple (flavour) 15 Banana (flavour) 16 Vanilla (flavour) 17 Croscarmellose sodium 18 Erythrosine lake l9 - Aerosil 20 Talc 21 Magnesium stearate EXAMPLE I (C): In an exemplary embodiment, the formulation of nutraceutical composition is shown below: · 21 S.No. Ingredients l VitaminC 2 Mecobalamin 40% Overages 3 Beet root extract 4 Sodium Nitrite 5 L-Citrulline 6 Hawthorn Berry 7 CoQ 10 8 Pearlitol 9 Xylitol 10 Pharmatose DCL-15 11 Citric acid anhydrous 12 Sucralose 13 Mixed Fruit (flavour) 14 Pineapple (flavour) 15 Banana (flavour) 16 Vanilla (flavour) 17 Croscarmellose sodium 18 Erythrosine lake 19 Aerosil 20 Talc 21 Magnesium stearate One key concept in the neutraceutical compostion is having an appropriate overage. The term refers to the use of kinetic data on nutrient stability to calculate the amount of added nutrient so that the anticipated level of the nutrient at the end of the product's shelf life is in accordance with the level indicated on the label. In the present neutraceutical composition Mecobalamin overages by40%. According to above mentioned embodiments the neutraceutical compostion is prepared in the ranges as given b e1o w: Ingriedients Best Mode Range Lower Range (mg) Upper Range (mg) Vitamin C 40mg 20 100 Hawthorn Berry 150mg 100 300 Beetroot 200mg 100 400 COQ 10 50mg 50 100 Methylcobalamin 750 meg Omcg 1000 meg L- Citruline 70 mg 50 200 Sodium Nitrite 10mg 5 50 22 y-. The said neutraceutical composition is prepared bydispensing the ingredients at ambient conditions followed by passing of Vitamin. C, Beet root extract, Sodium Nitrite, L-Citrulline, Hawthorn Berry, Pearlitol, Xylitol, Pharmatose DCL-15, .Croscarmellose sodiumthrough Mechanical sifter · #40SS screen, Mecobalamin, All Flavors, sucralose, Citric acid, Aerosilthrough Mechanical sifter #60SS screen and Erythrosine lake colorthrough Mechanical sifter #80SS screen. Further the compression of the blend is performed in an octagonal blender for a time period of 10-15 minutes.After blending, this mixture is again mixed with Magnesium stearate and talc_, which has been already been sifted through #60 SS screen. The final mixture is blended compressed and packaged in moisture protective containers or films that offer exceptional barrier properties against moisture and oxygen penetration. According to present invention the critical step is the preparation of a nutraceutical composition comprising of Vitamin C, Hawthorn Berry, Beetroot, L- Citruline, Sodium Nitrite and Methylcobalamin in an oral disintegrating tablet form which is solved by the procedure disclosed in the present invention. Referring to figure 5, in one of the preferred embodiments with disClosed ingredients, equipmentsand their respective amounts as disclosed in exemplary formulations, the manufacturing process is disclosed thereof. Method of manufacturing: I. Weighing Check weights of all active and inactive raw materials as per the manufacturing formula. II. Sifting Sift Vitamin C, Beet root extract, Sodium Nitrite, .L-Citrulline, Hawthorn Berry, Pearlitol, Xylitol, Pharmatose DCL-15, Croscarmellose sodium through a mechanical sifter fitted with #40 SS screen. Sift Mecobalamin, All Flavors, sucralose, citric acid anhydrous, Aerosil through #60 SS screen separately. Sift erythrosine lake color through #80 SS screen. Collect the sifted material in polythene lined drum and label accordingly. III. Mixing Load the sifted material of above step in Octagonal blender and mix for 10-15 minutes. IV. Lubrication Sift magnesium stearate and talc through 60# SS screen and add in. mixed material in octagonal blender and mix for 5 minutes. Unload the mixed lubricated blend in polythene lined drums: Intirpate QC department for in process sampling and bulk analysis. Dehumidifiers required during whole process. Compression stage: Punch size 16 mm flat round punch Upper punch : plain Lower punch : plain With corresponding dies Description Light purple round biconvex plain on both sides uncoated tablet. Weight 1445 mg 23 Thickness 5.5mm Dosage- Initially 2 tab in a day in divided dosages After 30 days 1 tab daily Dosage should be adjusted as per Plasma nitrite or it can be checked by Nitrite testine strips. NiLrite testing strips are works on griess reagent principle;they diagnose nitrite level from plasma. Saliva Nitric Oxide Test Strips are hand held strips that rapidly turn from white to deep pink based on the amount of a surrogate marker for Nitric Oxide. Within seconds, you are e1ble to selfcheck and assess your Nitric Oxide status by comparing the intensity of the color on the Nitric Oxide Test strips to a color chart found on the Berkeley Test tube. The Nitric Oxide test strip collects and measures the precursor and by-product of Nitric Oxide. On one end of the strip is the saliva absorption pad. Place absorption pad ("saliva here" on strip) on your tongue for 3-5 seconds to collect saliva. Fold the absorption pad against the test pad for 3-5 seconds. After pressing together, gently, release and watch the test pad change to a reddish color within 45 seconds. If the pad remains white with a hue of light pink, you have low Nitric Oxide levels; however, if the pad shows a deep pinkish-red, your levels are elevated. On the outside of the Berkeley Test canister a color chart is found. Simply hold your Nitric Oxide test strip to the color chart to assess your Nitric Oxide status. Nitric Oxide Test Strips are based on the amount of a metabolite for Nitric Oxide. It is not a diagnostic or genetic test. It simply increases after a few hours with the consumption of leafy green foods. The metabolite, nitrite, is a well-accepted marker for Nitric Oxide and a stable molecule that is both a source and by product of Nitric Oxide. Nitric Oxide is a critically important molecule in our body that maintains blood vessel health. Nitric Oxide is not to be confused· with nitrous oxide or nitric acid. The neutraceutical compositions of the present invention have many possible usages such as, Blood Circulation improvement, Improvement in lipid profile, Adjuvant therapy in mild to moderate hypertension, Nutritional Supplementation during diabetes, Anti-ageing. While at least some exemplary embodiment has been presented in the foregoing detailed description of the invention, it should be appreciated that a vast number of variations exist. It should also be appreciated that the exemplary embodiment are not intended to limit the scope, applicability, or configuration of the invention in any way. It is being understood that various changes may be made in the function and arrangement of elements described in an exemplary embodiment without departing from the scope of the invention.

We claim: I. A nutraceutical composition, comprising: a nitrate source provided in an amount ranging from I 00 to 400 mg; a nitrite source provided in an amount ranging from 05 to 50 mg; L-citrulline provided in an amount ranging from 50 to 200 mg; Vitamin C provided in an amount ranging from 20-100 mg; Methylcobalamin provicied in an amount ranging from 0-1000 meg; CO Q 10 provided in an amount ranging from 50-100 mg; wherein the nutraceutical composition is in oral disintegrating tablet form. 2. The neutraceutical composition as claimed in claim 1, wherein the nitrite source is prefer<1bly Sodium nitrite. 3. The neutraceutical composition as claimed in claim 1, wherein the nitrate source is pref~::rably Beet root extract. 4. A nutraceutical composition as claimed in claim 1, wherein the nutraceutical composition comprises of 40 mg of Vitamin C, 150 mg of Hawthorn Berry, 200 mg of Beetroot, 70 mg L- Citruline, 10 mg of Sodium Nitrite, 750 meg of Methylcobalamin and 50 mg of COQ 10. 5. The neutraceutical composition as claimed in claim 1, wherein the neutraceutical composition · comprises, Pearlitol, Xylitol, Sucralose, Pharmatose DCL-15, Croscarmellose sodium, Citric acid anhydrous, Erythrosine lake, Aerosil, Talc, Magnesium stearate and flavors. 6. A method for preparing the neutraceutical composition as claimed in claim I, comprising the steps of, Weighing of all active and inactive raw materials as per the manufacturing formula; Sifting Vitamin C, Beet root extract, Sodium Nitrite, L-Citruiline, Hawthorn Berry, Pearlitol, Xylitol, Pharmatose DCL-15, Croscarmellose sodium through a mechanical · sifter fitted with #40 SS screen; Sifting Mecobalamin, All Flavors, sucralose, citric acid anhydrous, Aerosil through mechanical sifter #60 SS screen separately; Sifting Erythrosine Lake color through mechanical sifter #80 SS screen; Collecting the sifted material in polythene lined drum and label accordingly; Loading the sifted material in Octagonal blender and mixing for 10-15 minutes; Sifting magnesium stearate and talc through mechanical sifter 60# SS screen and adding in mixed material in octagonal blender and mix for 5 minutes; Unloading the mixed lubricated blend in polythene lined drums; Compressing and packing the final mixture.