FIELD OF THE INVENTION

The present invention relates to a medicament to control and reduce hypertension. More specifically, the present invention is to provide a medicament consists of a group of amino acids, antioxidant, magnesium glycinate, plant flavonoid, coenzyme Q10, vitamins, fish oil, garlic, and potassium chloride to control and reduce hypertension by means of attenuating heightened sympathetic nervous system while increasing the endogenous production and bioavailability of quintessential vasodilatory signaling molecule nitric oxide. The said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to be consumed, without common side effects associated with mainstream antihypertensive drugs.

BACKGROUND OF THE INVENTION

Heart disease and stroke are the world’s biggest killers, accounting for a combined 15 million deaths in year 2015. These diseases have remained to be the leading causes of death globally in the last 15 years. The major modifiable risks factor for heart disease and stroke is hypertension (high blood pressure). Hypertension is a medical condition in which higher than normal amount of blood pressure force exerts against the inside wall of blood vessels. Hypertension usually does not show any symptom for many years until vital organs such as the kidneys have been severely damaged. Symptoms of kidneys damage such as lethargy, poor appetite, and fatigue do not show up until 70% - 80% of kidneys functions are lost. Hypertension is also a major cause of other severe diseases such as peripheral artery disease, aortic aneurysm, and chronic kidney disease. Elevated blood pressure has been linked to shortened life expectancy.

Blood pressure, measured in mm Hg (millimeter mercury') _» is usually measured and reported in 2 parameters. The first parameter is the systolic pressure - the highest blood pressure reading when the heart pumps. The second parameter is the diastolic pressure - o the lowest blood pressure reading when the heart relaxes. The third parameter, when applicable, is the mean arterial pressure - the averaged blood pressure calculated based on the systolic and diastolic pressure. The hemodynamics formula for blood pressure is: Blood Pressure - Cardiac Output x Systemic Vascular Resistance. Blood pressure is a result of cardiac output (blood volume the heart pumps out per minute) multiplies with systemic vascular resistance (the resistance against blood flow primarily influenced by blood vessels circumference). The value difference between the systolic pressure and diastolic pressure is known as the pulse pressure, which primarily influenced by arterial stiffness - an independent risks factor that is positively linked to the risks of stroke.

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has classified that hypertension begins when the resting systolic blood pressure is at or above 140 mm Hg, or resting diastolic blood pressure is at or above 90 mm Hg. Prehypertension - blood pressure at or above 121/S 1 mm Hg but at. or below 139/89 mm Hg, has been found to increase the incidence of stroke. Blood pressure previously defined as normal (120 to 129/80 to 84 mm Hg) or borderline ( 130 to 139/85 to 89 mm Hg) compared to those with optimal blood pressure (<120/80 mm Hg) is associated with increased risks of cardiovascular disease.

Hypertension itself is not a disease instead, it is a symptom of an underlying disease or medical condition that causes a mismatch between cardiac output and systemic vascular resistance. There are more than 70 known causes of hypertension. Some of the common causes include, but not limited to: Heightened sympathetic nervous system, overactive renin angiotensin aldosterone system, endothelium dysfunction (vasodilator deficiency), oxidative stress, high intracellular sodium levels, sedentary' lifestyle, elevated hematocrit levels, hyperthyroidism, sleep apnea, coarctation of the aorta, blood vessels hardening, kidneys disorders, and more.

The body uses various systems to regulate short-term and long-term systemic blood pressure. They are the Autonomic Nervous System (short-term) and the Renin Angiotensin Aldosterone System (long-term). The autonomic nervous system has two divisions: Sympathetic Nervous System (excitatory) - which relies on glutamate as excitatory neurotransmitter, and Parasympathetic Nervous System (inhibitory) - which relies on gamma aminobutyric acid (GABA) as inhibitory neurotransmitter. High ratio of glutamate over GABA in the brain from excessive consumption of monosodium glutamate (MSG) commonly found in processed food, can stimulate the sympathetic nervous system and trigger the release of adrenaline (epinephrine) and noradrenaline (norepinephrine) front the adrenal glands to increase heart rate, heart contractility, and generalized vasoconstriction. This pathway leads to higher cardiac output and higher systemic vascular resistance, therefore effectively increases systemic blood pressure. Injections of glutamate (MSG) on animals were also associated with rapid increase in plasma adrenaline, noradrenaline, heart rate, and blood pressure.

The renin angiotensin aldosterone system regulates long-term systemic blood pressure via systemic vasoconstriction (narrowing of blood vessels) and fluid retention in the body. The renin angiotensin aldosterone system can he activated under various conditions such as; Sympathetic nervous system stimulation (stress, anxiety, fight, fear, and excessive glutamate over GABA levels in the brain), low blood flow to the kidneys (afferent arteriole vasoconstriction, renal artery stenosis, systemic hypotension), an low plasma sodium delivery to distal tubules of the kidneys. The renin angiotensin aldosterone system is one of the main factors in the pathophysiology of cardiovascular disease that is associated with fibrosis, hyperplasia, inflammations, and oxidative stress. These effects have a critical role in initiating and the progression of hypertension, atherosclerosis, and heart failure. Angiotensin 11 - the active peptide hormone produced by the renin angiotensin aldosterone system, is a highly potent vasoconstrictor on the systemic vascular system, which also stimulates the sympathetic nervous system, and stimulates the release of hormone aldosterone to increase fluid retention in the body via sodium reabsorption by the kidneys. Angiotensin II plays a major role in vascular damage, atherosclerosis, hypertension, growth induction, cell migration, mitosis of vascular smooth muscle cells, and Increases synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and the myocardium. An increase in systemic vascular resistance through vasoconstriction, along with increased blood volume in the cardiovascular system through fluid retention by the kidneys effectively increases systemic blood pressure.

It Is now universally acknowledged that some of the main contributors to hypertension are: Heightened sympathetic nervous system, overactive renin angiotensin aldosterone system, endothelium dysfunction (vasodilator nitric oxide deficiency), oxidative stress, and high intracellular sodium levels.

Heightened Sympathetic Nervous System: The sympathetic nervous system can be stimulated under various conditions such as: Stress, anxiety, fight, fear, and excessive glutamate over GABA levels in the brain. Monosodium glutamate (MSG), the common food additive in processed food, can heighten the sympathetic nervous system rapidly. Since the kidneys are innervated by the sympathetic neurons of the autonomic nervous system via the celiac plexus and splanchnic nerves, heightened sympathetic nervous system increases the release of adrenaline from the adrenal medulla. This released adrenaline is then bound to beta-receptors located in the heart to increase heart rate and heart contractility, which increases cardiac output. Adrenaline also induces generalized vasoconstriction when bound to alpha ! -receptors located in blood vessels, therefore increases systemic vascular resistance. Heightened sympathetic nervous system can effectively increase systemic blood pressure.

Overaetive Renin Angiotensin Aldosterone System: Upon sympathetic nervous system stimulation, the released adrenaline from the adrenal medulla induces vasoconstriction on the kidneys' afferent arterioles, which reduces blood flow to the kidneys. The kidneys perceive such condition as systemic hypotension due to the low- perfusion pressure on their stretch receptors in the vascular wall. This in turn activates the renin angiotensin aldosterone system, starting with the release of enzyme reni to convert plasma protein angiotensinogen to angiotensin 1, Angiotensin f is then converted to angiotensin P by Angiotensin Converting Enzyme (ACE). Angiotensin II - the active peptide hormone produced by the renin angiotensin aldosterone system, is a highly potent vasoconstrictor on the systemic vascular system, which also stimulates the sympathetic nervous system, and stimulates the release of hormone aldosterone to increase fluid retention in the body via sodium reabsorption by the kidneys. Overactive renin angiotensin aldosterone system can effectively increase systemic blood pressure.

Endothelium Dysfunction (vasodilator nitric oxide deficiency): Hypertension is linked to the inabilit of the vascular network to dilate adequately through the L~ arginine nitric oxide pathway, which is associated with endothelium dysfunction. The endothelial layer is the tissue that forms a single layer of cells lining over blood vessels, and can be impaired in functionality' or damaged when it is exposed to chronic conditions such as: High blood pressure, diabetes, smoking, and physical inactivity. One of the main functions of the endothelial layer is to produce nitric oxide through the L- arginine nitric oxide pathway to regulate arterial tone. Nitric oxide is a molecular gas, which functions as a quintessential vasodilator/ signaling molecule for blood vessels to dilate. Nitric oxide is synthesized by enzyme Nitric Oxide Synthase (NOS) that oxidizes guanidine nitrogen of amino acid L-arginine to release nitric oxide from the endothelial layer, and leaving L-citrul!ine as a byproduct. L~eitruiline is then recycled back to becoming L-arginine again with two enzymes: Argininosuccinate Synthetase and Argininosuccinate Lyase. The released nitric oxide diffuses to the surrounding vascular smooth muscle cells, activates enzyme Soluble Guany!yl Cyclase (sGC) that leads to an increase in intracellular Cyclic Guano sine Monophosphate (cGMP), which then lowers Intracellular calcium ion levels, causing relaxation of the vascular smooth muscle cells surrounding the periphery of blood vessels, inducing vasodilation. Dilated blood vessels have wider circumference, therefore decrease systemic vascular resistance, increase blood flow', reduce workload on the heart, and effectively lower systemic blood pressure inadequate levels of nitric oxide can contribute to hypertension, even vasoconstrictors such as: Adrenaline, noradrenaline (norepinephrine), and angiotensin II are not excessively high. Endothelium dysfunction can effectively increase systemic blood pressure.

Oxidative Stress: Hypertension is associate with an increase in oxidative stress and a decrease in the hioavaiiahiiity of nitric oxide. Oxidative stress occurs when the bod cannot neutralize the production of harmful reactive oxygen species with antioxidants. Reactive oxygen species are chemically reactive molecules produced by the body as a result of normal cellular metabolism and environment factors such as: Cigarette smoke, and air pollutions, increasing amount of evidence suggests that oxidative stress plays a key role in the pathogenesis of hypertension. Reactive oxygen species include: Superoxide anion, hydroxyl radicals, hydrogen peroxide, hypochlorous acid, and peroxynitrite. Antioxidants are classified as either endogenous or exogenous. Endogenous antioxidants include: Superoxide dlsmutase, alpha llpoic acid, coenzyme Q10, catalase, glutathione, and glutathione peroxidase. Exogenous antioxidants include: Carotenoids, vitamin C, vitamin E, and polyphenols. Reactive oxygen species superoxide anion determines the bioavailability and biosynthesis of nitric oxide. Since nitric oxide plays an important role in arterial vasodilation via the L-arginine nitric oxide pathway, it Is therefore important to maintain good bioavailabiiity of nitric oxide from being degraded by reactive oxygen species such as superoxide anion. Superoxide anion causes vital changes in the intracellular signal transduction systems, which marks an Increased production of inositol triphosphate, and decreased production of cyclic guanosine monophosphate (cGMP) in the vascular smooth muscle cells. This favors vasoconstriction, which increases systemic vascular resistance, decreases blood flow·', increases workload on the heart, and effectively increases systemic blood pressure. The bioavailabiii ty of nitric oxide, which is the major vasodilator that lowers systemic blood pressure, relies heavily on the redox status. Therefore, regulation of reducing and oxidizing (redox) state is of utmost importance for cell viability, activation, proliferation, as well as organ function. Adequate levels of antioxidants (endogenous & exogenous) are crucial to neutralize excessive reactive oxygen species and maintain good bioavailabiiity' of nitric oxide.

High Intracellular Sodium Levels; High intracellular sodium levels increase cells’ sensitivity towards sympathetic nervous system stimulation. This is because calcium follows sodium, and high dietary· sodium intake increases accumulation of intracellular calcium, which heightens wall tension of blood vessels and favors vasoconstriction upon sympathetic nervous system stimulation. Sodium also attracts water via osmosis, leading to blood volume expansion. These extra blood volumes are predominantly redistributed in the cardiopulmonary area, leading to an increment in both venous return and cardiac output, in short, sodium heightens adrenergic activity, increases systemic vascular resistance via vasoconstriction, and elevates cardiac output. High intracellular sodium levels can effectively increase systemic blood pressure.

In view of the above, there are five hypothetical ways to act on these five main contributors to hypertension: Attenuate sympathetic nervous system stimulation by reducing cortical neuron excitation; reduce angiotensin 11 production by minimizing activation of the renin angiotensin aldosterone system; increase the bioavailability of quintessential vasodllatory signaling molecule nitric oxide with precursors; reduce oxidative stress by increasing the hioavailahiiity of antioxidants; and decrease intracellular sodium levels via sodium excretion.

Currently, hypertension therapy is substantially based on the oral administration of antihypertensive drugs from various classes such as, hut not limited to: Thiazide diuretics, beta blocker, angiotensin converting enzyme inhibitor, angiotensin II receptors blocker, and calcium channel blocker. These antihypertensive drugs contain active ingredients that either reduces cardiac output or/and decreases systemic vascular resistance. The former works by reducing heart rate (negative chronotropic), heart contractility (negative inotropic), and fluid volume (diuretic) in the body while the later works by relaxing the periphery' smooth muscle cells that surround blood vessels. However, these anti h p tensive drugs are actually unable to cure hypertension because they do not treat the causes of hypertension. In other words, they treat the symptoms but not the causes of hypertension.

This is evident from the fact that hypertensive individuals are required to take antihypertensive drugs on a daily basis, for the rest of their lives. Upon discontinuation of these drugs, blood pressure often spikes to levels higher than levels prior drugs therapy. One possible explanation is that by treating the symptoms, but not the causes of hypertension with these drugs, the untreated causes of hypertension grew and became more severe over time. Ibis further explains why these drugs may lose their efficacy over time. To combat such situations, clinicians often resort to either increase the dosage of prescribed antihypertensive drugs, or/and introduce additional antihypertensive drug(s) from other classes. This increases not only the cost of medications, but also severely exposes the hypertensive individual to a wider range of side effects, severity, and contraindications. These side effects may range from persistent dry cough to the pathogenesis of severe life threatening diseases such as: Diabetes, renal impairment, liver dysfunction, and heart failure. These diseases induced by antihypertensive drugs may not show any symptom until irreversible damages have occurred.

Common known side effects of antihypertensive drugs (by classes) are, but not limited to:

Thiazide Diuretics - abnormal heart rhythm, blurred vision, dizziness, headache, hypokalemia, increased blood sugar, increased uric acid, itching, loss of appetite, sexual dysfunction, stomach upset, sun sensitivity, weakness, etc.

Beta Blocker - blurred vision, confusion, depression, diarrhea, disorientation, dizziness, fatigue, hair loss, hallucinations, headache, heart block, heart failure, insomnia, masked low blood glucose among diabetics, muscle cramps, nausea, rash, weakness, etc.

Angiotensin Converting Enzyme Inhibitor - abnormal taste bud, allergies, angioedema, chest pain, cough, decreased white blood cells, dizziness, elevated blood urea nitrogen and creatinine, headache, hyperkalemia, increased uric acid, kidney failure, liver dysfunction, pancreatitis, rash, sun sensitivity, weakness, etc.

Angiotensin O Receptors B!ocker ~ abnormal taste bud, allergies, angioedema, cough, decreased blood platelets, decreased white blood cells, diarrhea, dizziness, fatigue, headache, hyperkalemia, indigestion, kidney failure, liver failure, orthostatic hypotension, rash, rhabdomyolysls, sexual dysfunction, upper respiratory tract infection, etc.

Calcium Channel Blocker - constipation, dizziness, edema, gums overgrowth, headache, hypotension, liver dysfunction, nausea, rash, sexual dysfunction, etc. These antihypertensive drugs also contribute to other side effects when interact with other drugs.

The presence of other drugs or chemicals which elevate blood pressure directly or through secondary phenomena (drug interactions, renal impairment) can produce resistant hypertension (blood pressure remains above goal despite treatment with three or more antihypertensive medications at or near maximal doses), increase antihypertensive drugs requirement, or cause loss of blood pressure control in previously well controlled hypertensive individuals.

In view" of the known side effects and contraindications of antihypertensive drugs, there is therefore, the need for an alternative medicament to improve the performance of controlling and reducing hypertension among the involved groups. In view of the foregoing, the present invention has developed a medicament consists of a group of amino acids, antioxidant, magnesium glycinate, plant fiavonoid, coenzyme Q10, vitamins, fish oil garlic, and potassium chloride to control and reduce hypertension by means of attenuating heightened sympathetic nervous syste while increasing the endogenous production and bioavailability of quintessential vasodilators· signaling molecule nitric oxide. I ^' he said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to he consumed, without common side effects associated with mainstream antihypertensive drugs.

SUMMARY

The aim of the present invention is to provide a medicament consists of a group of amino acids, antioxidant, magnesium glycinate, plant fiavonoid, coenzyme Q10, vitamins, fish oil, garlic, and potassium chloride to control and reduce hypertension by means of attenuating heightened sympathetic nervous system while increasing the endogenous production and bioavailability of quintessential vasodilatory signaling molecule nitric oxide. The said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to be consumed, without common side effects associated w-'lth mainstream antihypertensive drugs. Within this aim, an object of the present invention is to provide a medicament that is capable of acting in a differentiated but simultaneous manner on the normal biochemical processes that regulate systemic blood pressure, Each of the components in the medicament has specific amount (in range) to effectively control and reduce hypertension. in one embodiment, the medicament may further comprise pharmaceutical excipient, carrier or diluent thereof. The medicament is administered to human through oral administration method to control and reduce hypertension.

Another object of the present invention is to provide a method for manufacture of a medicament for use to control and reduce hypertension, comprising the steps of introducing a group of amino acids, antioxidant, magnesium glyeinate, plant flavonoid, coenzyme 10, vitamins, fish oil, garlic, and potassium chloride in a therapeutically effective amount into the medicament.

A further object, features and advantages of the present invention will be readily apparent from the following descriptions,

BRIEF DESCRIPTIONS OF THE DRAWINGS/FIGURES

The accompanying drawings, which are included to provide further understanding of the present invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the present invention and together with the descriptions serve to explain the principles of the present invention.

Figure 1 shows the neurohormonal hypertension pathway;

Figure 2 shows the list of components In Formulation 1 ;

Figure 3 show's the list of components in Formulation 2; Figure 4 shows the summary report of the efficacy of the medicament according to one embodiment of the present invention;

Figure 5 shows the systolic pressure of Group 1 and Group 2 over the 16 weeks of the studv;

Figure 6 shows the systolic pressure changes of Group 1 and Group 2 after the 16 weeks of the study;

Figure 7 shows the diastolic pressure of Group 1 and Group 2 over the 16 weeks of the study;

Figure 8 shows the diastolic pressure changes of Group 1 and Group 2 after the 16 weeks of the study;

Figure 9 shows the mean arterial pressure of Group 1 and Group 2 over the 16 weeks of the study;

Figure 10 shows the mean arterial pressure changes of Group 1 and Group 2 after the 16 weeks of the study;

Figure 1 1 shows the pulse pressure of Group 1 and Group 2 over the 16 weeks of the studv;

Figure 12 shows the pulse pressure changes of Group 1 and Group 2 after the 16 weeks of the study;

Figure 13 shows the heart rate of Group 1 and Group 2 over the 16 weeks of the study; and

Figure 14 shows the heart rate changes of Group 1 and Group 2 after the 16 weeks of the studv. DETAILED DESCRIPTIONS OF THE PRESENT INVENTION

In the following detailed descriptions, reference is made to various specific embodiments in which the present invention may be practiced. These embodiments are described with sufficient details to enable those methods in the present invention to be practiced and it is to be understood that other embodiments may be employed and that structural and logical changes may be made without departing from the scope of the present invention.

Heart disease and stroke are the world’s biggest killers, accounting tor a combined 15 million deaths in 2015. These diseases have remained to be the leading causes of death globally in the last 15 years. The major modifiable risks factor for heart disease and stroke is hypertension (high blood pressure). Hypertension is a medical condition in which higher than normal amount of blood pressure force exerts against the inside wall of blood vessels. Hypertension itself is not a disease. Instead, it is a symptom of an underlying disease or medical condition that causes a mismatch between cardiac output and systemic vascular resistance. Elevated blood pressure has been linked to shortened life expectancy.

Currently, hypertension therapy is substantially based on the oral administration of antihypertensive drugs from various classes such as, but not limited to: Thiazide diuretics, beta blocker, angiotensi converting enzyme inhibitor, angiotensin II receptors blocker, and calcium channel blocker. However, these antihypertensive drugs are actually unable to cure hypertension because they do not treat the causes of hypertension. Common known side effects of antihypertensive drugs include, but not limited to: Abnormal heart rhythm, abnormal taste bud, allergies, angioedema, blurred vision, chest pain, confusion, constipation, cough, cramps, decreased blood platelets, decreased white blood cells, depression, diarrhea, disorientation, dizziness, drowsiness, edema, elevated bun and creatinine, fatigue, gums overgrowth, hair loss, hallucinations, headache, heart block, heart failure, hyperkalemia, hypotension, increased blood sugar, increased uric acid, indigestion, insomnia, itching, kidney failure, liver dysfunction, liver failure, loss of appetite, lo or high blood sugar, masked low blood glucose among diabetics, muscle cramps, nausea, orthostatic hypotension, pancreatitis, rash, rhabdomyolysis, sexual dysfunction, stomach upset, sun sensitivity’, upper respiratory tract infection, vomiting, weakness, etc.

In view of the known side effects and contraindications of antihypertensive drugs, there is therefore, the need for an alternative medicament to improve the performance of controlling and reducing hypertension among the involved groups. In view of the foregoing, the present invention has developed a medicament consists of a group of amino acids, antioxidant, magnesium glycmate, plant flavono , coenzyme Q10, vitamins, fish oil, garlic, and potassium chloride to control and reduce hypertension by means of attenuating heightened sympathetic nervous system while increasing the endogenous production and bioavailabiiity of quintessential vasodilatory signaling molecule nitric oxide. The said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to he consumed, without common side effects associated with mainstream antihypertensive

It is now universally acknowledged that some of the main contributors to hypertension are: Heightened sympathetic nervous system, overactive renin angiotensin aldosterone system, endothelium dysfunction (vasodilator nitric oxide deficiency), oxidative stress, and high intracellular sodium levels. in view of the above, there are five hypothetical ways to act on these five main contributors to hypertension: Attenuate sympathetic nervous system stimulation by- reducing cortical neuron excitation; reduce angiotensin II production by minimizing activation of the renin angiotensin aldosterone system; increase the bioavailabiiity- of quintessential vasodilatory signaling molecule nitric oxide with precursors; reduce oxidative stress by increasing the bioavailabiiity of antioxidants; and decrease intracellular sodium levels via sodium excretion.

The aim of the present invention is to provide a medicament consists of a group of amino acids, antioxidant, magnesium glycinate, plant fiavonoid, coenzyme Q10, vitamins, fish oil, garlic, and potassium chloride to control and reduce hypertension by means of attenuating heightened sympathetic nervous system while increasing the endogenous production and bioavailability of quintessential vasodiiatory signaling molecule nitric oxide. The said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to be consumed, without common side effects associated with mainstream antihypertensive drugs. Within this aim, an object of the present invention is to provide a medicament that is capable of acting in a differentiated but simultaneous manner on the normal biochemical processes that regulate systemic blood pressure. Each of the components in the medicament has specific amount (in range) to effectively control and reduce hypertension.

The inventor of the present invention has invented a more efficient method to control and reduce hypertension by intervening the normal biochemical processes that induce hypertension (Figure 1). This is made possible by earlier intervention on the neurohormonal hypertension pathway, compared to other classes of antihypertensive drugs such as, but not limited to: Angiotensin converting enzyme inhibitor, angiotensin !I receptors blocker, and renin inhibitor. This method begins by suppressing excessive cortical neuron excitations (commonly found among hypertensive individuals) by attenuating the binding of prominent excitatory neurotransmitter glutamate to glutamate receptor found in the brain, with the administration of the amino acid of L-theanine, which in turn decreases sympathetic nervous system stimulation, leading to reduced production of adrenaline (adrenaline increases cardiac output, generalized vasoconstriction, and vasoconstriction on the renal afferent arterioles), thereby reduces activation of the renin angiotensin aldosterone system, therefore attenuates the production of renin, angiotensin 1, angiotensin II, aldosterone, vasopressin, NADPH oxidase, and reactive oxygen species. This method decreases systemic blood pressure by suppressing chronically elevated cardiac output, and decreases systemic vascular resistance by attenuating the production of vasoconstrictive hormones such as adrenaline, noradrenaline, and angiotensin II. The inventor of the present invention has discovered that resorting to a combined administration of a combination of amino acids (L~theanine with L-citrulline) can control and reduce hypertension more effectively, by: Suppressing chronically elevated cardiac output, decreasing systemic vascular resistance by lowering production of vasoconstrictive hormones, and decreasing systemic vascular resistance by increasing the production of quintessential vasodiiatory signaling molecule nitric oxide via increasing the bioavailability of plasma arginine with L-citrulline.

Besides, the inventor of the present invention has also discovered that resorting to a combined administration of L-theanine with L-citrulline and plant flavonoid can create synergetic and therapeutic effects in the control and regulation of hypertension, with a higher efficacy and a longer half-life. This is achieved by: Suppressing chronically elevated cardiac output, decreasing systemic vascular resistance by lowering production of vasoconstrictive hormones, decreasing systemic vascular resistance by increasing the production of quintessential vasodiiatory' signaling molecule nitric oxide via increasing tbe bioavailability of plasma arginine with L~ citrulline, and increasing the biosynthesis and bioavailability of nitric oxide from been hampered or degraded by superoxide anions with plant flavonoid.

Thus, to provide an alternative to control and reduce hypertension, the present invention has developed a medicament (1Q) consists of a combination of amino acids (11); antioxidant (12); magnesium glycinate (13); plant flavonoid (14); eoenzyme Q10 (15); a combination of vitamins B (16); vitamin D3 (17); fish oil (18); garlk (19); and potassium chloride (20). The medicament (10) according to the present invention may comprise of any pharmaceutical excipient, carrier or diluent. Besides, the medicament (10) is administered to human through oral administration method. in a specific embodiment, the present invention is to provide a medicament (10) that is able to control and reduce hypertension by means of attenuating heightened sympathetic nervous syste while increasing the endogenous production and bioavailabiiity of quintessential vasodiiator signaling molecule nitric oxide. The said medicament is not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to be consumed, withou common side effects associated with mainstream antthypertensive drugs. in one embodiment, the combination of amino acids (11) are preferably selected from the group consisting of L-ci trull ne (101) with the amount selected from the range of 10 mg to 19800 mg; L-proline (102) with the amount selected from the range of 10 mg to 3600 mg; L-carniiine (103) with the amount selected from the range of 10 mg to 6000 mg; L-theanine (104) with the amount selected from the range of 10 g to 1200 mg; and L-glycine (105) with the amount selected from the range of 10 mg to 18000 mg. In the present invention, the selected amino acids with the selected range of amount in the medicament (10) help to reduce and control hypertension.

The amount of L-citrulline (101) is preferably selected from the range of 10 mg to 19800 mg. Oral ingestion of L-citrulline (101) can he converted to L-arginine with enzyme argininosuccinate synthetase and argininosuccinate lyase in the nitric oxide cycle. L-arginine is the precursor of nitric oxide synthesis. Nitric oxide is a gas that is produced by the endothelium layer located inside the wall of blood vessels, and functions as a signaling molecule for blood vessels to relax hence dilate. While oral ingestion of L-arginine leads to an increase in plasma arginine, ingested L-arginine is hampered by extensive pre-systemic elimination due to intestinal arginase activity. On the other hand, oral ingestion of L-citrulline (101) is readily absorbed and at least in part converted to L-arginine with enzyme argininosuccinate synthetase and argininosuccinate lyase in the nitric oxide cycle. Hence, oral ingestion of L-citrulline (101) can increase plasma arginine indirectly for nitric oxide synthesis. This makes oral ingestion of L-citrulline (101) a more effective way to increase plasma arginine, when compared to oral ingestion of L-arginine. In the present invention, the L-eitrulline (101) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of L-proline (102) is preferably selected fro the range of 10 mg to 3600 mg. L-proline (102) is an amino acid found in the body. It can be synthesized through the breaking down of I., -glutamate, as well as obtainable from dietary sources such as meat, fish, cabbage, eggs, soy, and supplements. L-proline (102) is the precursor of hydroxyproline, in which hydroxyproline, L-glycine (105), and vitamin C are part of the building blocks of collagen. Collagen makes up the walls of arteries, veins, and capillaries throughout the body, as well as strengthening and maintaining their elasticity. Hardened blood vessels are linked to low collagen levels, causing high blood pressure and elevated pulse pressure, a major independent risk factor for heart disease and stroke. In the present invention, the L-proiine (102) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of L-camitine (.103) is preferably selected from the range of 0 mg to 6000 rng. f. -carnitine (103) is an amino acid found in the body. It can be synthesized from amino acids L-lysine and L -methionine, as well as obtainable from dietary' sources such as red meat, dairy products, and supplements. L -carni tine (103) plays a role in the transportation of long chain fatty acids such as triglycerides into mitochondria for energy production. This process allows the body to turn fat into energy and helps to lower triglyceride level in the blood. In the present invention, the L-camitine (103) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of L~theanine (104) is preferably selected from the range of 10 mg to 1200 mg. L-theanine (104) is an amino acid found In plant and fungal species such as Camellia Sinensis. It is obtainable from dietary' sources such as green tea, black tea, and supplements. Due to its unique ability to cross the blood brain barrier and its similar structure as glutamate (prominent excitatory' neurotransmitter), L-theanine (104) reduces stress by blocking the binding of glutamate to glutamate receptors found in the brain. This inhibits cortical neuron excitation and reduces stimulation on the sympathetic nervous system. L-theanine (104) lowers stress level when measured using stress marker salivary immunoglobulin-A, In the present invention, the L-theanine (104) with the selected range of amount in the medicament (10) helps to reduce and control hypertension. The amount of L-glycine (105) is preferably selected from the range of 10 mg to 18000 mg L-glyc e (105) is the simplest form of amino acid and it is obtainable from dietary sources such as fish, meat, dairies, legumes, and supplements. L-glycine (105) involves in the biosynthesis of structural proteins such as collagen and elastin. Elastin functions as a medium for pressure wave propagation to support blood flow. Reduced elastin level is linked to aorta stiffening. Aorta stiffening is one of the causes of high blood pressure, as well as elevated pulse pressure - a major risks factor for heart disease and stroke. In the present invention, the I, -glycine (105) wit the selected range of amount in the medicament (10) helps to reduce and control hypertension.

!n another embodiment, the antioxidant (12) is ascorbic acid (106) with the amount selected from the range of 10 mg to 6000 rag. Vitamin C, also known as ascorbic acid (106), is a water-soluble vitamin which is obtainable from dietary' sources such as fruits, particularly citrus fruits like oranges and kiwifruit, vegetables, as well as supplements, Vitamin C is required for the formation of collage and blood vessels. It helps strengthening and maintaining elasticity of blood vessels. Hardened blood vessels are linked to lo collagen level, causing high blood pressure and elevated pulse pressure, a major independent risks factor for heart disease and stroke. Vitamin C is a powerful aqueous-phase exogenous antioxidant that reduces oxidative stress and potent against systemic vascular inflammation, which is often measured with biomarker high sensitivity C-reaetive protein (hs-CRP). Systemic vascular inflammation is linked to cardiovascular disease such as coronary artery disease. Vitamin C has been reported to possess modest effects on reducing systolic and diastolic blood pressure among hypertensive individuals. Added to this, it is well established that vitamin C inhibits oxidation of low-density lipoprotein cholesterol, therefore reducing atherosclerosis. Vitamin C helps improve the bioavai!abiUty of nitric oxide for vasodilation by neutralizing free circulating reactive oxygen species. In the present invention, the ascorbic acid (186) with the selected range of amount in foe medicament (10) helps to reduce and control hypertension.

The amount of magnesium glycinate (13) is preferably selected from the range of 10 mg to 4800 mg. Magnesium glycinate (13) is the magnesium salt of glycine, consisting about 14.1% dement magnesium by mass. Magnesium glycmate (13) has a relatively high absorption rate in the body, when compared to other magnesium salt such as magnesium oxide. Magnesium is an essential dietary element and it is obtainable from dietary sources such as spinach, legumes, seeds, nuts, whole grains, as well as supplements. Magnesium deficiency is very common in developed countries after vitamin D. Deficiency in magnesium intake may cause neural excitation, leading to elevated systemic blood pressure and reduced insulin sensitivity. Magnesium deficiency changes calcium metabolism, creating high intracellular calcium ions, which favors vasoconstriction. High intracellular calcium ions, along with high cellular sodium- potassium ratio occur when cellular magnesium becomes too low, and the Mg-ATP driven sodium-potassium pump and calcium pump can become functionally impaired. While the pathogenesis of hypertension is associated with chronic activation of the renin angiotensin aldosterone system and an overactive sympathetic nervous system, changes in intracellular ions such as sodium, potassium, magnesium, and calcium also contribute to hypertension. Hypertension can develop when the ratio of sodium-potassium becomes too high, either due to high dietary' sodium intake or/and with low dietary potassium intake, or indirectly through magnesium deficiency, which causes a pseudo potassium deficit. Low level of magnesium concentrations is linked to oxidative stress, pro-inflammatory state, endothelial dysfunction, platelet aggregation, insulin resistance, and hyperglycemia. Magnesium from magnesium glycinate (13) can act as a natural calcium channel blocker, increases nitric oxide for vasodilation, an Improves endothelial dysfunction. Magnesium intake is also linked to effective prevention an treatment on cardiovascular diseases such as coronary heart disease, ischemic stroke, and cardiac arrhythmias. In the present invention, the magnesium glycinate (13) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The plant fiavonoid (14) is preferably selected from the fiavonoid extracted from the plant of Vitis Vinifera , with the amount selected from the range of 10 mg to 1200 mg. Plant fiavonoid (14) is a source of procyanklins, a class of polyphenols found in plants, which functions as a potent antioxidant to neutralize free radicals. It is obtainable from supplements. In the present invention, the plant flavonoid (14) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The coenzyme QIO (15) is preferably selected from the group consisting of ubidecarenone or/and ubiquinone, with the amount selected from the range of 4 mg to 600 mg. Coenzyme Q10 (15) is a potent fat- soluble antioxidant, and it neutralizes free radicals that cause cell death, cell membrane damage, and DNA tampering. Coenzyme Q10 (15) is obtainable from dietary sources such as organs meat (kidneys, liver, heart), beef, mackerel, sardines, and supplements. In some form of hypertension, superoxide radicals that inactivate nitric oxide are overproduced, causing low bioavailability of nitric oxide therefore impair vasodilation. Coenzyme Q10 (15) with its antioxidative effects may prevent the inactivation of nitric oxide by superoxide radicals. Alternatively,coenzyme Q10 (15) may boost the production of prostaglandin prostacyclin (PGI2) - a potent vasodilator and inhibi tor of platelet aggregation, or it ma enhance the sensitivity of arterial smooth muscle to prostaglandin prostacyclin (PG12), or both. Coenzyme Q10 (15) deficiency is linked to cardiovascular disease, heart failure, muscle dystrophies, parkin sou s disease, cancers, and diabetes. In the present invention, the coenzyme Q10 (15) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The combination of vitamins B (16) are selected from a group consisting of vitamin B6 (.1.07) preferably pyridoxine with the amount selected from the range of 1 mg to 90 mg; vitamin B9 (108) preferably folic acid with the amount selected from the range of 0.01 mg to 1.20 mg: and vitamin B12 (109) preferably methy!cobalamin with the amount selected from the range of 0.01 mg to 1.50 mg,

Vitamin B6 (107) i a eofaclor for enzymes involved in one of the two pathways for the metabolism of homocysteine. Remethylation of homocysteine to methionine requires vitamin B9 (108) and vitamin B12 (109). Folic acid supplements increase the activity of this pathway to lower fasting homocysteine levels. Evidence suggests that elevated homocysteine levels may cause: Vascular endothelial cell damage, impaired endothelium dependent vasodilation due to decreased nitric oxide activity, increased oxidation and arterial deposition of low-density lipoprotein (LDL), increased platelet adhesiveness, and activation of the clotting cascade. Decreased vitamin B6 (107) concentrations are also associated with elevated plasm levels of C-reactive protein (CRP). CRP is an indicator of inflammation that is implicated in increased cardiovascular morbidity. In the present invention, the combination of vitamins B (16) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The vitamin D3 (17) is preferably cholecalciferpl with the amount selected from the range of 1 international unit (IU) to 8000 III. Vitamin D3 (17) plays a critical role in the regulation of renin angiotensin aldosterone system, therefore influences systemic blood pressure regulation. When compared with vitamin D3 (17) sufficient individuals, those who are deficient and insufficient in vitamin Ό3 (17) ha greater plasma angiotensin II levels, and a trend for higher plasma renin activity. Added to this, the activity' of the renin angiotensin aldosterone system in the kidneys, as measured by the renal plasma flow in response to angiotensin 0 infusion, was greate in vitamin D3 (17) deficient individuals than in vitamin D3 (17) sufficient individuals. In the present invention, the vitamin D3 (17) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of fish oil (18) is preferably selected from the range of 1 mg to 10000 mg. The specific amount of fish oil (18) consists in the medicament (10) helps to protect against the development of atherosclerosis and heart disease. Fish oil (18) also exerts Its cardiovascular protective effects by lowering blood pressure, blood triglyceride, and very-low-density lipoprotein (VI., DL). In the present invention, the fish oil (18) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of garlic (19) is preferably selected from the range of 1 mg to 3000 mg. Polysulfides derived from garlic (19) stimulate the production of vascular gasotransmitter hydrogen sulfide (II2S) and support the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation hence vasodilation, leading to lower systemic blood pressure. Dietary and genetic factors influence the efficiency of hydrogen sulfide (¾$) and nitric oxide signaling pathways, therefore may contribute to hypertension, Sulfur deficiency may aggravate hypertension, and it can be alleviated with organosulfur compounds derived from garlic (19). in the present invention, the garlic (19) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

The amount of potassium chloride (20) is preferably selected from the range of 1 mg to 6000 rag. Sodium, in the form of table salt (sodium chloride), i abundant in the modem diet particularly from restauran an processed food. High intracellular sodium levels increase ceils’ sensitivity towards sympathetic nervous system stimulation. This is because calcium follows sodium, and high dietary sodium intake increases accumulation of intracellular calcium, which heightens wall tension of blood vessels and favors vasoconstriction upon sympathetic nervous system stimulation. Sodium attracts water via osmosis, leading to blood volume expansion. These extra blood volumes are predominantly redistributed in the cardiopulmonary area, leading to an increment in both venous return and cardiac output In short, sodium heightens adrenergic activity, increases systemic vascular resistance via vasoconstriction, and elevates cardiac output. High intracellular sodium levels can effectively increase systemic blood pressure. The addition of potassium chloride (20) as one of the crucial components in the medicament (10) helps by enhancing sodium excretion from the body. In the present invention, the potassium chloride (20) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.

To further illustrate the present invention in greater details and not by way of limitation, the following examples will be given. These examples are merely illustrations and should not limit the scope of the claims herein. The ordinary skilled in the art will recognize other variations, modifications and alternatives. EXAMPLE I

Figure 2 discloses the preferred amount of each component in the medicament (10) The medicament (10) for use to control and reduce hypertension according to the present invention can be produced according to fee Formulation 1 illustrated in Figure 2 Please take note feat, the amount of ingredients listed in Figure 2 is only the best mode amount. The medicament (10) for use to control and reduce hypertension according to the present invention can also be produced by introducing the combination of amino acids (II); antioxidant (12); magnesium glycinate (13); plant flavonoid (14); coenzyme Q10 (15); a combination of vitamins B (16); vitamin D3 (17); fish oil ( 18); garlic (19); and potassium chloride (20) in any therapeutically effective amount into fee medicament (10).

EXAMPLE 2

Alternatively, fee medicament (10) for use to control and reduce hypertension according to the present invention can also be produced according to the Formulation 2 illustrated in Figure 3 without introducing the combination of vitamins B (16); fish oil (18); garlic (19); and potassium chloride (20) in any therapeutically effective amount into the medicament (10).

The efficacy of the medicament (10) in controlling and reducing hypertension ha been verified by conducting a randomized prospective study on 51 subjects over a time frame of 16 weeks, in which the medicament (10) was administered orally- according to Formulation 2 as illustrated in Figure 3, one serving per day, on everyday basis over a period of 16 weeks on fee treatment group. Inclusion criteria for this study were general good health, prehypertension (121-139 mm Hg/S 1-89 mm Hg) and stage 1 hypertension ( 140-159 mm fig/90-99 mm Hg), The evaluation of general good health involved clinical evaluation and medical history, full blood test panel to rule out abnormalities in hematology, diabetes, kidney function, liver function, lipid profile, thyroid function, and electrocardiogram.

The study included a management plan with dietary changes (reduction of sodium, monosodium glutamate, sugar, caffeine, alcohol) and lifestyle changes (regular exercise, improve sieep time, reduce smoking). No other supplements, vitamins, or drugs were used. The management plan was assigned to all 51 subjects, and these 51 subjects were then divided into 2 groups:

Group 1 (25 subjects) - treatment group with the medicament (10) according to Formulation 2 as illustrated in Figure 3, one serving per day, on everyday basis with management plan over a period of 16 weeks.

Group 2 (26 subjects) - control group with management plan only over a period of 16 weeks.

Group 1 consists of 25 subjects (13 males, 12 females), group 2 consists of 26 subjects (15 males, 1 1 females). The age range of these 51 subjects was 27 - 64 and the mean age of group 1 was 41, and group 2 was 43, Compliance was above 90% in group 1 , and above 93% in group 2.

Both groups were studied concurrently for a period of 16 weeks, in which systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate were measured and recorded using hospital grade Welch AUyn Connex® Vital Signs Monitor model VSM 64MXPX. Results were evaluated at the end of week 4, 8, 12, 16 to evaluate the efficacy of the medicament (10) in controlling and reducing hypertension.

At the end of week 4, group 1 and group 2 showed reduction in systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate when compared to the numbers obtained during the enrollment of the study ^' Fhe summary report of the efficacy of the medicament (10) is shown in Figure 4. However, the magnitude of reduction was significantly profound in group 1 compared to group 2, in which systolic pressure decreased -24 mm Hg (group 1) vs. decreased -5 mm Hg (group 2), diastolic pressure decreased -8 mm Hg (group 1) vs. decreased -3 mm Hg (group 2), mean arterial pressure decreased -13 mm Hg (group 1 ) vs. decreased -3 mm Hg (group 2), pulse pressure decreased -16 mm Hg (group 3 ) vs. decreased -2 mm Hg (group 2), heart 2a rate decreased ~5 BFM (group 1) vs. decreased ~2 BPM (group 2).

At the end of week 8, group 1 and group 2 continued to show reduction in systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate when compared to the numbers obtained at the end of week 4 of the study (Figure 4). The magnitude of reduction remained significantly profound in group 1 compared to group 2, in which systolic pressure decreased -7 mm Hg (group I) vs. decreased -4 mm Hg (group 2), diastolic pressure decrease -5 mm Hg (group 1 ) vs. decreased ~2 mm Hg (group 2), mean arterial pressure decreased -6 mm Hg (group 1) vs. decreased -3 mm Hg (group 2), pulse pressure decreased -2 mm Hg (group 1) vs, decreased -2 mm Hg (group 2), heart rate decreased -4 BPM (group 1} vs. decreased -1 BPM (group 2).

At the end of week 12, group 1 and group 2 showed reduction/unchanged in systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate when compared to the numbers obtained at the end of week 8 of the study (Figure 4). The magnitude of reduction remained significantly profound in group 1 compared to group 2, in which systolic pressure decreased -4 mm Hg (group 1 ) vs, decreased -2 mm Hg (group 2), diastolic pressure decreased -4 mm Hg (group 1) vs. decreased -1 mm Hg (group 2), mean arterial pressure decreased -4 mm Hg (group 1) vs. decreased -1 mm Hg (group 2), pulse pressure unchanged 0 mm Hg (group 1 ) vs. decreased -1 mm Hg (group 2), heart rate decreased -4 BPM (group 1) vs. decreased -1 BPM (group 2).

At the end of w'eek 16, group 1 and group 2 continued to show reduction/unchanged in systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate when compared to the numbers obtaine at the end of week 12 of the study (Figure 4). The magnitude of reduction remained profound in group 1 compared to group 2, in which systolic pressure decreased -3 mm Hg (group 1 ) vs, decreased -1 mm Hg (group 2), diastolic pressure decreased -4 mm Hg (group 1} vs. decreased -1 mm Hg (group 2), mean arterial pressure decreased -3 mm Hg (group 1) vs decreased ~1 mm Hg (group 2), pulse pressure increased +1 mm Hg (group 1 ) vs, unchanged 0 mm Hg (grou 2), heart rate decreased ~3 BFM (group 1) vs, decreased -1 BFM (group 2).

To summarize, at the end of the 16 weeks, randomized prospecti ve study on 51 subjects on the efficacy of the medicament (10) according to Formulation 2 as illustrated in Figure 3, one serving per day, on everyday basis with management plan over a period of 16 weeks, hemodynamics numbers from parameters such as systolic pressure, diastolic pressure, mean arterial pressure, pulse pressure, and heart rate were compared against the initial numbers obtained during the enrollment of the study (Figure 4). The total changes are: Systolic pressure decreased -38 mm Hg (group 1 ) vs. decreased -12 mrn Fig (group 2); diastolic pressure decreased -21 mm Fig (group 1) vs. decreased -7 m Hg (group 2); mean arterial pressure decreased -26 mm Hg (group 1 } vs. decreased -8 mm Hg (group 2); pulse pressure decreased -17 mm Hg (group I) vs, decreased -5 mm Hg (group 2); heart rate decreased -16 BPM (group 1 ) vs. decreased -5 BPM (group 2). No side effects was reported during the entire period of the study, and formulation tolerability was very good.

The efficacy of the medicament (10) according to Formulation 2 as illustrated in Figure 3 in controlling and reducing hypertension on 25 subjects out of the 51 subjects In a 1 weeks randomized prospective study is reported in Figure 4 and further illustrated in Figure 5 to Figure 14.

Data from this study suggests that complementing the medicament (10) according to Formu!ation 2 as illustrated in Figure 3, one serving per day, on everyday basis along with healthy dietary and lifestyle changes can create synergetic effects in the control and regulation of hypertension by means of attenuating heightened sympathetic nervous system while increasing the endogenous production and bioavail ability of quintessential vasodi!atory signaling molecule nitric oxide. This is achieved by: suppressing chronically elevated cardiac output decreasing systemic vascular resistance by lowering production of vasoconstrictive hormones, decreasing systemic vascular resistance by increasing the production of quintessential vasodilators' signaling molecule nitric oxide via increasing the bioavailability of plasma arginine with L-citrul line, and increasing the biosynthesis and bioavailability of nitric oxide from been hampered or degraded by superoxide anions with plant flavonoid. 'J

The medicament (10) not only able to control and reduce hypertension effectively, but also consists of natural resources that are safe to be consumed, without common side effects associated with mainstream antihypertensive drugs, making it a nondrug option that is better accepted than mainstream antihypertensive medications.

List of references

World Health Organization. The Top 10 Causes of Death. Retrieved from http://ww'w.who. t''mediacentre/factsheets/fs310/en/

American Heart Association. Understand Your Risks to Prevent a Heart Attack. Retrieved from http://www\heart.org/HBARTOR€f/Gmrditions/HeartAttack/Unde rstandYourRiskstoP reventaHeartAttaek/Understand-Your~Risks~to-Prevent-a-Heap

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Merck Manual High Blood Pressure (Hypertension). Retrieved from htip://www.merckmanuais cora/home/heart-and-b!ood~vessei-disorders/hlgh-btood~ pre ssure/hi gh-biood-pressure