WO2019117702A1 - Médicament pour contrôler et réduire l'hypertension - Google Patents

Médicament pour contrôler et réduire l'hypertension Download PDF

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WO2019117702A1
WO2019117702A1 PCT/MY2018/000019 MY2018000019W WO2019117702A1 WO 2019117702 A1 WO2019117702 A1 WO 2019117702A1 MY 2018000019 W MY2018000019 W MY 2018000019W WO 2019117702 A1 WO2019117702 A1 WO 2019117702A1
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medicament
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Yuen KAM FAII
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Kam Faii Yuen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/60—Fish, e.g. seahorses; Fish eggs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 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.
  • 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.
  • 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.
  • GABA gamma aminobutyric acid
  • 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.
  • 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).
  • ACE Angiotensin Converting Enzyme
  • 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.
  • sGC Soluble Guany!yl Cyclase
  • cGMP Cyclic Guano sine Monophosphate
  • 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 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.
  • Attenuate sympathetic nervous system stimulation by reducing cortical neuron excitation 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • antihypertensive drugs are actually unable to cure hypertension because they do not treat the causes of hypertension.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • L-arginine 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.
  • 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.
  • oral ingestion of L-citrulline (101) can increase plasma arginine indirectly for nitric oxide synthesis.
  • L-citrulline (101) helps to reduce and control hypertension.
  • 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.
  • 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.
  • 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
  • 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.
  • the I, -glycine (105) wit the selected range of amount in the medicament (10) helps to reduce and control hypertension.
  • 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)
  • 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.
  • the ascorbic acid (186) with the selected range of amount in foe medicament (10) helps to reduce and control hypertension.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the coenzyme Q10 (15) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.
  • 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 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.
  • LDL low-density lipoprotein
  • CRP C-reactive protein
  • 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.
  • Vitamin D3 (17) sufficient individuals, those who are deficient and insufficient in vitamin ⁇ 3 (17) ha greater plasma angiotensin II levels, and a trend for higher plasma renin activity.
  • 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).
  • 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 (3 ⁇ 4$) 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).
  • 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.
  • potassium chloride (20) as one of the crucial components in the medicament (10) helps by enhancing sodium excretion from the body.
  • the potassium chloride (20) with the selected range of amount in the medicament (10) helps to reduce and control hypertension.
  • 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).
  • 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.
  • Group 1 25 subjects
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.

Abstract

L'invention concerne un médicament (10) étant constitué d'une combinaison d'acides aminés (11); d'antioxydant (12); de glycinate de magnésium (13); de flavonoïde végétal (14); de coenzyme Q10 (15); d'une combinaison de vitamines B (16); de vitamine D3 (17); d'huile de poisson (18); d'ail (19); et de chlorure de potassium (20) pour une utilisation pour contrôler et réduire l'hypertension. Chacun des composants dans le médicament (10) a une quantité spécifique (dans la plage) pour contrôler et réduire efficacement l'hypertension.
PCT/MY2018/000019 2017-12-16 2018-05-24 Médicament pour contrôler et réduire l'hypertension WO2019117702A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030108624A1 (en) * 1997-02-04 2003-06-12 Kosbab John V. Compositions and methods for prevention and treatment of chronic diseases and disorders including the complications of diabetes mellitus
KR20060069850A (ko) * 2003-09-05 2006-06-22 마티아스 라트 비타민 ｃ, 마그네슘, 녹차 추출물을 포함하는 심장혈관계질환을 억제하기 위한 약제 조성물
WO2013122188A1 (fr) * 2012-02-15 2013-08-22 協和発酵バイオ株式会社 Agent pour prévenir ou améliorer un dysfonctionnement de l'endothélium vasculaire
CN104940933A (zh) * 2015-06-15 2015-09-30 青岛大学附属医院 一种用于预防治疗心血管疾病的药物
JP2017012144A (ja) * 2015-10-09 2017-01-19 株式会社東洋新薬 血流改善組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030108624A1 (en) * 1997-02-04 2003-06-12 Kosbab John V. Compositions and methods for prevention and treatment of chronic diseases and disorders including the complications of diabetes mellitus
KR20060069850A (ko) * 2003-09-05 2006-06-22 마티아스 라트 비타민 ｃ, 마그네슘, 녹차 추출물을 포함하는 심장혈관계질환을 억제하기 위한 약제 조성물
WO2013122188A1 (fr) * 2012-02-15 2013-08-22 協和発酵バイオ株式会社 Agent pour prévenir ou améliorer un dysfonctionnement de l'endothélium vasculaire
CN104940933A (zh) * 2015-06-15 2015-09-30 青岛大学附属医院 一种用于预防治疗心血管疾病的药物
JP2017012144A (ja) * 2015-10-09 2017-01-19 株式会社東洋新薬 血流改善組成物

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