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WO2008031322A1 - Application d'un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de leonurus utilisé en tant que cholinomimétique - Google Patents

Application d'un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de leonurus utilisé en tant que cholinomimétique Download PDF

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Publication number
WO2008031322A1
WO2008031322A1 PCT/CN2007/002456 CN2007002456W WO2008031322A1 WO 2008031322 A1 WO2008031322 A1 WO 2008031322A1 CN 2007002456 W CN2007002456 W CN 2007002456W WO 2008031322 A1 WO2008031322 A1 WO 2008031322A1
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WO
WIPO (PCT)
Prior art keywords
motherwort
extract
disease
cholinergic
acetylcholinesterase inhibitor
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PCT/CN2007/002456
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English (en)
Chinese (zh)
Inventor
Shuping Hao
Hui Hao
Shuyu Xiao
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Shuping Hao
Hui Hao
Shuyu Xiao
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Publication of WO2008031322A1 publication Critical patent/WO2008031322A1/fr

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    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/533—Leonurus (motherwort)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to the use of motherwort extract, in particular to the use of motherwort extract as a acetylcholinesterase inhibitor of a cholinergic agent in the pharmaceutical field.
  • Lemium is a Labiatae plant, formerly known as Yu Wei, traditional understanding and indications: irregular menstruation, dysmenorrhea, amenorrhea, postpartum blood stasis, water, blood in the urine, red eyes and swelling, dizziness and pain. Yuweizi is the mature fruit of Motherwort. It has a sweet taste, sweetness, slight cold, and enters the liver. Its function of promoting blood circulation and regulating menstruation is the same as that of motherwort. It has the functions of clearing the liver and improving eyesight, promoting blood circulation and qi, and is used for clinical use in redness, swelling or pain. Eye disease.
  • Motherwort extract includes the existing on the market: Motherwort granules, motherwort cream, motherwort syrup, motherwort oral liquid, motherwort capsule, ⁇ , motherwort injection, people's understanding of the above-mentioned motherwort extract is mainly limited to the traditional treatment of motherwort range.
  • motherwort C 13 H 21 0 5 N 3
  • motherwort total base, and stachydrine have been reported in the existing literature to have direct excitatory effects on various animals in the uterus, which can cause uterine contraction frequency, amplitude, and Increased tension, and the effect of promoting blood circulation, stopping bleeding.
  • the main ingredient of ⁇ , ⁇ is motherwort Ning (Le 0 mirinine, C 1() H 14 0 3 N 2 ), stachysine and oleic acid.
  • the main components of oleic acid are: linoleic acid (42.62 % ), linolenic acid (29.93%), oleic acid (20.23%), palmitic acid (5.40%), stearic acid (1.57%), etc., in addition to 17 amino acids and 24 mineral elements, and vitamins
  • ⁇ is an extract of ⁇ , which contains motherwort, stachydrine and oleic acid.
  • the therapeutic effect of guanwei oil as a drug has not been reported.
  • the object of the present invention is to provide a new use of motherwort extract, specifically related to motherwort extract, motherwort granules, motherwort cream, motherwort syrup, motherwort oral liquid, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ granules , ⁇ ⁇ ⁇ , ⁇ ⁇ syrup, ⁇ ⁇ oral liquid, ⁇ ⁇ capsule, motherwort injection as a choline acetylcholine esterase inhibitor in the pharmaceutical field.
  • the present invention relates to motherwort extract: motherwort cream, motherwort syrup, motherwort granules, motherwort oral solution, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ , ⁇ syrup Agent, Qiwei oral liquid, Qiwei capsule, and motherwort injection as acetylcholinesterase inhibitors of cholinergic drugs.
  • the present invention relates to the main active ingredients in the extract of Motherwort: motherwort base, motherwort, motherwort total base, motherwort A, stachydrine or a pharmaceutically acceptable salt thereof as an acetylcholinesterase inhibitor of the cholinergic agent.
  • the motherwort extract is used as a cholestyramine inhibitor of acetylcholine in the preparation and treatment of Alzheimer's disease, Alzheimer's disease, Parkinson's disease, rickets, schizophrenia, and Rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, progressive muscular atrophy, varicose veins of the lower extremities, thromboangiitis obliterans, acne, psoriasis, vitiligo, goose wind, hypertension, coronary heart disease, hyperlipidemia , cardiovascular and cerebrovascular disease, aplastic anemia, purpura, disseminated intravascular coagulation, irregular menstruation, cancer, leukemia, hepatitis B, jaundice hepatitis, cirrhosis, glaucoma, cataract, tinnitus, deafness, hair loss,
  • the method for treating and preventing a disease comprising administering to a patient a therapeutically effective amount of an active ingredient selected from the group consisting of motherwort, motherwort, motherwort total base, motherwort A, and water stasis. a mixture of a base or a mixture thereof or a pharmaceutically acceptable salt thereof or a mixture of the two.
  • the motherwort extract is used as a acetylcholinesterase inhibitor drug for a cholinergic agent, and a therapeutically effective dose of the active ingredient is administered at a dose of 0.005 to 0.4 g/kg per day per day.
  • the active ingredient of the motherwort extract ⁇ or motherwort extract is added as an additive to an edible oil or a rubbing cosmetic or a washing daily necessities or an oral care daily necessities.
  • the ratio of the additive to the additive is 1/5000 to 1/10.
  • the following will separately use the motherwort granules, motherwort cream, motherwort sugar granules, motherwort oral liquid, motherwort capsules, ⁇ ⁇ ⁇ , ⁇ ⁇ oil, ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ , ⁇ Pharmacological tests and results of Weiwei, Yuwei syrup, Qiwei oral liquid, Qiwei capsule and motherwort injection to illustrate its new use in the pharmaceutical field.
  • the above five substances have the same pharmacological effects, and the difference is only in the amount used and the time of marked effect.
  • the lower limbs are inactive or paralyzed, but they are conscious and have no effect on body temperature, breathing, and heart rate. The symptoms can return to normal after about four hours, and no death is observed for three days.
  • acetylcholinesterase inhibitors were screened by Ellman analysis. Add human acetylcholinesterase (hAchE) in the buffer to the test chemical / TCM extract, then add Acetylthiocholine (ATCI) substrate and Ellman's reagent (5 ' 5 - disulfide - double - (2-nitrate) Benzoate), DTNB :). By releasing the thiocholine pair AchE inhibitory activity was monitored and the thiocholine was subsequently reacted with DTNB to form a bright yellow product. The optical density of the resulting color developing product was measured using a spectrophotometer.
  • test results are shown in Figure 1.
  • the 50Mg I ml of motherwort water extract inhibited MChE activity by more than 80%.
  • motherwort extract of motherwort extract motherwort cream, motherwort syrup, motherwort oral liquid, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ syrup
  • the anti-acetylcholinesterase activities of the active ingredients of Qiwei Oral Liquid, Qiwei Capsule and Yimucao Injection were tested. They were motherwort (C10H14O3N2), motherwort (C13H2105N3, molecular weight 311.33), motherwort total alkali, Motherwort A, stachydrine (C7H13N02, molecular weight 143.0). All of these are from the China National Institute for the Control of Pharmaceutical and Biological Products of the China Food and Drug Administration.
  • the selected active ingredient is dissolved in 50% DMS0 below, and 100% DMS0 is not recommended in this assay because it reduces enzyme activity. Ellman analysis was performed on the selected active ingredients, motherwort base, motherwort, motherwort total base, motherwort A, and stachydrine, and the 10-fold dilution was performed at a maximum concentration of 40 M (Fig. 2).
  • motherwort base, motherwort, motherwort total base, motherwort A, and stachydrine showed strong AChE inhibition, and their IC50 were about 5-8 mm (Fig. 2).
  • hBchE butyl Acetylcholinesterase
  • the toxicity of selected major MchE inhibitors was tested by MTT assay. Considering that only metabolically active cells can remove the tetrazolium salt MTT to form the formazen dye, the 0D detection at 540 nm is directly proportional to the number of viable cells.
  • the term "pharmaceutically acceptable salt” is defined as a soluble salt of an inorganic or organic acid such as motherwort sulfate, motherwort acetate, stachysine hydrochloride or the like.
  • active ingredient as used in the present invention is defined as the motherwort extract of the motherwort extract, motherwort cream, motherwort syrup, motherwort oral solution, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ Wei Chong, Qi Wei Ointment, Yu Wei Syrup, Qiwei Oral Liquid, Qiwei Capsule, Motherwort Injection or Motherwort Alkaloids: Motherwort Ning, Motherwort, Motherwort Total Alkaloids, Motherwort A, Stachyphylline or its Drugs An acceptable salt or a mixture of the two.
  • the motherwort granules, motherwort cream, motherwort syrup, motherwort oral liquid, motherwort capsule, and glutinous rice granules of the present invention are all available products, and those skilled in the art can obtain them through existing production processes.
  • the dosage forms of the following motherwort extracts are ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ ⁇ , ⁇ ⁇ ⁇ , ⁇ ⁇ syrup, ⁇ ⁇ oral liquid, ⁇ ⁇ capsule, and motherwort injection, which are the same as the existing corresponding dosage forms.
  • the active ingredient alkaloids therein and their extraction in pharmaceutically acceptable salts are known in the art, and the stachysine may also be derived from stachys.
  • the plant of the present invention is preferably selected from the group consisting of motherwort whole grass, and the motherwort extract used in the present invention is selected from the group consisting of ⁇ ( ⁇ ).
  • the extract of Motherwort includes an extract of water extract, ethanol extract, pressed extract, or other existing methods.
  • the extract of Motherwort or the alkaloid, alkali salt or a mixture thereof of the above motherwort is made into a pharmaceutically acceptable carrier, and the "pharmaceutically acceptable carrier” refers to an excipient or adjuvant used in the pharmaceutical to promote the processing of the active ingredient into a preparation.
  • the preparation can be administered orally, intramuscularly, intraperitoneally, subcutaneously or intravenously. Preferred are the preparations, especially those such as tablets, ointments, granules, syrups, capsules, pills, granules and injections, and suitable solutions.
  • Suitable excipients for use in the present invention include fillers such as polysaccharides such as lactose or sucrose, mannitol or sorbitol, cellulose derivatives, magnesium sulfate, calcium phosphate such as tricalcium phosphate or calcium hydrogen phosphate, and such as corn starch , a binder of starch paste such as wheat starch.
  • Suitable adjuvants for use include fluid conditioning agents and lubricants such as talc, silica, stearic acid.
  • the extract of the present invention can be formulated into an injection method such as intravenous, subcutaneous and intramuscular injection, an oral preparation, a suppository or a sublingual tablet. It is prepared by methods generally accepted in the art.
  • compositions such as injections, sublingual tablets, tablets, syrups and capsules. Stabilizers and preservatives may be added as needed in the preparation.
  • the active ingredient or composition when administered orally, it may be in the form of a tablet or a capsule, or an aqueous solution or suspension.
  • carriers which are usually used include lactose, mannitol and corn starch, and a lubricant such as magnesium stearate is usually added.
  • the active compound is administered in a dry gelatin capsule in a dry form, or in a suitable gel or liquid carrier, such as liquid polyethylene glycol or cross-gel, in a soft gelatin capsule. .
  • the motherwort alkaloids motherwort base, motherwort, motherwort total base, motherwort A, stachydrine, and sputum oil are used as acetylcholinesterase inhibitor drugs for cholinergic drugs for health purposes
  • the ratio of the above alkaloid or the eucalyptus oil is added to the edible oil, and the addition ratio of the additive and the edible oil is 1/5000 to 1/10, and the preferred addition ratio is 1/500 to 1/50.
  • ⁇ ⁇ oil contains alkaloids motherwort, stachydrine and vitamin A-like substances, 24 mineral elements and a variety of amino acids, which are added to edible oil for long-term consumption. It has the function of positively regulating the human body, improving immunity, supplementing nutrients and trace elements, and achieving health care effects.
  • the effective dosage of the active ingredient is about 005-0. 4 mg/kg ⁇ day.
  • the dosage of the active ingredient is about 005-0. 4 mg/kg ⁇ day.
  • Dosing is preferably administered at a dose of 0.01 mg to 1.0 mg per day per day. It is taken every morning and evening, and after taking it for three days, it is taken in half, and seven days is a course of treatment.
  • an effective therapeutic dose or "effective dose” as used herein means an effective dose of the active ingredient to achieve its intended purpose.
  • the dosage should be varied depending on the condition, sex, age and weight of the patient, the method of administration, the time and interval of administration, and the characteristics, modulation, type, specific effective component, and the like of the pharmaceutical preparation.
  • acetylcholinesterase inhibitor can inhibit the degradation of acetylcholine in the synaptic cleft space, and can enter the cell, and can excite the cholinergic nerve endings, release Ach, and form the concentration of acetylcholine.
  • the sorghum can be reduced to normal, and the low can rise to normal, which can promote the restoration of the relative stable balance of various physical and chemical factors in the human body.
  • acetylcholine has neuroprotective effects on muscarinic receptor and nicotinic receptor agonism.
  • Motherwort granules motherwort cream, motherwort syrup, motherwort oral solution, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ syrup, ⁇ oral solution, ⁇ M-like effects of the active ingredients of Motherwort Injection, Motherwort, Motherwort, Motherwort, Motherwort A and Stachyphylline:
  • Increased glandular secretion enhanced fluid regulation, hormones and nerves in the body
  • the secretion of the normal mass ratio increases or decreases, thereby forming a unified equilibrium mechanism between the two, and the function of the neuromodulation is strengthened by the regulation of body fluids, thereby forming a benign cycle of humoral regulation and neuromodulation.
  • the medicine of the invention can enhance the purifying function of blood, establish a long-term blood improvement mechanism, and the main leading role is: the liver is the largest gland of the human body, its secretion is strengthened, and the function of promoting liver biotransformation is strengthened.
  • Reducing the toxins in the blood causes the blood vessels of the body to dilate and relax, resulting in an increase in the volume of the blood vessels, and the volume of the blood vessels needs to be replenished in time, so the plasma
  • the colloid osmotic pressure is physically increased, and the extravascular blood is passively infiltrated into the capillaries.
  • the extravascular lymph and tissue fluids are also expanded accordingly, thereby improving the rheological parameters of the blood and reducing the viscosity of the blood. Delayed dissolution, blood toxins reduced or disappeared.
  • urinary tract detrusor contraction, sphincter relaxation, bladder emptying effect, showing diuretic swelling.
  • Vascular system There are vasodilatation and dilation combined with diuretic effect, which can lower blood pressure, comfortable head, smooth blood circulation, blood stagnation, and hemorrhagic depression.
  • Eye The pupil sphincter and ciliary muscle contract, shrinking the pupil, lowering the intraocular pressure, restoring eyesight, adjusting sputum (myopia), and partial comfort.
  • Gastrointestinal function Increased contraction amplitude and tension, increased gastrointestinal secretion, and enhanced digestive capacity.
  • N-like effect (1) Exciting ganglia!
  • ⁇ Receptors excite muscles, resist aging; (2) Excite the adrenal medullary N M receptor, adrenaline, norepinephrine release; this effect can excite the ⁇ 2 receptor of bronchial smooth muscle, so that the bronchus does not shrink too much avoid causing respiratory adverse reactions; (3) the excitement of skeletal muscle ⁇ ⁇ receptors: the performance of muscle contraction in the lesion site can establish a pinching effect of around efflux.
  • Head headband the head skeletal muscle mainly composed of the frontal muscle of the occipital front is caused by the contraction of the scalp aponeurosis causing the scalp tightness
  • the middle finger is the first finger, the back is strong and slightly painful, and the toe is intermittently slightly painful (the finger back muscle and the tendon sheath are pulled, this effect is remindative, protective, therapeutic)
  • neck back (caused by erector spinae mainly caused by excitatory contraction of the back muscle)
  • one or two saliva can be swallowed or swallowed from the mouth during sleep (caused by healthy secretion of salivary glands)
  • calf wrinkles Increased renal function, bladder smooth muscle contraction, diuretic effect caused by sphincter relaxation
  • the upper and lower eyelids are neurologically spurted for a while (the ganglion excitability causes nerve endings).
  • Motherwort extract Motherwort granules, motherwort cream, motherwort syrup, motherwort oral solution, motherwort capsule, ⁇ , ⁇ , ⁇ , ⁇ , ⁇ syrup, ⁇ oral solution
  • the active ingredients of Yiwei capsule, Yimucao injection or its extracts, such as motherwort, motherwort, motherwort total alkaloid, motherwort A and stachydrine, are all acetylcholinesterase inhibitors.
  • the medicament of the present invention is effective for treating Alzheimer's disease (AD), and has the functions of enhancing central cholinergic nerves, and slowing or stopping the formation of amyloid ⁇ -amyloid precursor protein ( ⁇ ) fragments.
  • AD Alzheimer's disease
  • ⁇ amyloid ⁇ -amyloid precursor protein
  • N-like effect the contraction of the frontal muscles of the forehead makes the upper part of the head form a tight-fitting effect, which can physically control abnormal brain activity, continuous contraction of skeletal muscle, and inhibition of pathological spastic contraction.
  • Acetylcholinesterase inhibitors have good physiological functions in protecting dopaminergic neurons and improving PD dyskinesia.
  • acetylcholinesterase By inhibiting acetylcholinesterase to prevent neuronal apoptosis, the patient's dopaminergic neurons are protected, and the function of the nigrostriatal dopaminergic nervous system is enhanced: inhibition of acetylcholinesterase can also increase endogenous acetylcholine Concentration, which regulates the release of striatal dopamine through nicotinic cholinergic ⁇ 2 receptor, achieves the effect of treating both PD and PD, especially for PD patients with dementia. Clinically, 10 drugs of Alzheimer's disease, 6 cases of Parkinson's disease, 3 cases of rickets, and 10 cases of schizophrenia were treated with the drug of the present invention, and all of them achieved satisfactory effects.
  • M-like effect enhanced by neuromodulation and humoral regulation and self-regulation, balance of body hormone levels, abundant tissue fluid, reduction of endotoxin, fresh blood, enhanced immunity, alleviation of syndromes, lower extremity edema is the main cause of acne the reason.
  • Pathology The central part of the limbs, the torso, the head surface of some pairs of nerves on the same section or adjacent to several sections, long-term loss of excitation (related to superior neurological factors), resulting in the corresponding nerve roots, nodes, tips
  • the inflammatory reflexes diminish or disappear, causing their counterparts to lose their neurotrophic protection and dominance control.
  • Symmetrical local functional waste lesions referred to as symmetrical changes, pathologically reflected in the joints are rheumatoid arthritis, reflected in the facial systemic lupus erythematosus, reflected in the body's muscle weakness, reflected in the muscle spindle For progressive muscular atrophy, plus Exogenous wind, cold, dampness, heat, poison and labor injuries make the symptoms worse.
  • the hemorrhagic disease stops, the blood disease is relieved and controlled, and the blood pressure is lowered by blood quality improvement, vasodilation, and diuretic effect.
  • the M effect relaxes the coronary artery, and the heart rate is relieved at a level of about 80 beats/min, which reduces the cardiac load and improves the symptoms of myocardial ischemia and hypoxia.
  • Motherwort, motherwort, motherwort total alkaloids, motherwort A, and stachydrine can improve myocardial blood supply, lower blood pressure, lower blood viscosity, inhibit platelet aggregation, anticoagulation, antithrombotic, and fibrinolysis.
  • Cardioprotective effects The production of a large number of free radicals and the lipid peroxidation induced by them are the main mechanisms of myocardial ischemia-reperfusion injury.
  • Myocardial ischemia is caused by ligation of rabbit coronary arteries.
  • Injection compared with the control group after 10 minutes of treatment, found that Motherwort can significantly reduce the content of malondialdehyde (MDA) in myocardial tissue and enhance superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX).
  • MDA malondialdehyde
  • SOD superoxide dismutase
  • GSH-PX glutathione peroxidase
  • Activity improving the ischemic manifestations of the ECG. It indicated that the active constituents of Leonurus extract could protect the activity of the antioxidant free radical enzyme system, inhibit the lipid reaction during myocardial ischemia and reperfusion, and alleviate myocardial cell damage caused by excessive oxygen free radicals.
  • Lowering blood viscosity 105 patients with blood hyperviscosity were treated with active ingredients of motherwort extract. Clinical symptoms such as dizziness, headache, insomnia and numbness were mostly alleviated. Blood rheology indicators such as whole blood specific viscosity (high cut and low cut), whole blood reduction specific viscosity (low cut) viscosity index, whole blood reduction specific viscosity (high cut), red blood cell deformability TK value, platelet aggregation rate, Both fibrinogen content and erythrocyte electrophoresis time were significantly improved, and the difference was significant before and after treatment (P ⁇ 0.05).
  • the active ingredient of Motherwort extract also enhances fibrinolysis, thereby inhibiting thrombus formation.
  • the mother of the motherwort extract of the present invention is fed with the active ingredient preparation, and then blood is taken from the common carotid artery for blood coagulation measurement.
  • the results show that the above preparation can inhibit platelet function, reduce internal and external coagulation function, and promote fibrinolytic activity.
  • ⁇ - ⁇ urokinase-type plasminogen activator
  • t-PA tissue plasminogen activator
  • the M-like action of the active ingredient of the motherwort extract of the present invention has the effects of improving blood quality, blood circulation, improving the immunity of the body, and effectively controlling the symptoms of skin, mucous membrane and internal organs caused by it.
  • the N-like effect causes the dorsal muscles of the erector spinae to excite and contract, and the central cholinergic nerves excite.
  • the spine, nerve center and spinal cord form a series of functional improvements, which restore and strengthen the hematopoietic system and blood cell functions.
  • M-like blood quality improved, reducing the occurrence of purpura.
  • 20 cases of aplastic anemia were treated with the drug of the invention, 17 cases were cured, 2 cases were obviously improved, 1 case was ineffective, the effective rate was 95%, and the cure rate was 85%.
  • Clinical treatment of 60 cases of purpura purpura phenomenon disappeared.
  • DIC disseminated intravascular coagulation
  • the drug of the present invention was administered three days before the operation, and no DIC symptom occurred in the operation room.
  • motherwort extract as an acetylcholinesterase inhibitor has a strong excitatory effect on the uterus, which can enhance the amplitude, frequency and tension of uterine contractions.
  • the active ingredient of the motherwort extract can make the rat uterus in the early stage of estrus change from a small amplitude irregular spontaneous contraction to a large amplitude regular contraction. The contraction can last for several hours, but it can be recovered after washing.
  • the excitability of cholinergic nerve can enhance the secretion function of the largest glandular liver in the human body, increase the bioconversion rate, promote the toxicity reduction and excretion rate of toxic substances in the body, thus reducing the toxins and impurities in the blood.
  • Increased fluids in certain parts including blood improve blood quality, blood is fresh and flawless, and blood vessels are dilated, blood circulation is smooth, menstrual pain is relieved or disappeared, and uterine smooth muscle function
  • the healthy contraction inhibits the permeability of the endometrial capillaries, so that the blood from the menstruation is not much more, and the amount of formation is moderate.
  • This drug preparation for treating tumor has a strong anti-tumor effect, and most of the cases in this group are In the advanced stage, the effective rate (PR+mR) was 42.9%, indicating that the growth of the tumor was inhibited, and if the course of treatment was prolonged, the effect could be increased.
  • the concentration of acetylcholine is increased, and the M effect can increase or decrease the ratio of hormones secreted by all glands including pituitary and adrenal medulla to Ach, thereby achieving hormone and neurotransmitter pairs.
  • the uniform balance of the interaction of cells enhances the protection and control of nerves on cells, thereby reducing the probability of cell mutation and mutation.
  • the relative balance between the ligands of the cell receptors can also inhibit the infiltration of the secretions of cancer cells into normal cells, thereby reducing the rate of cancer spread.
  • the enhancement of glandular secretion activity and the long-term continuous excitatory contraction of smooth muscle and skeletal muscle also reduce the space of the placeholder from the physical point of view and inhibit the development of the tumor.
  • the drug of the present invention has a good positive regulation effect on the human body, and the active ingredient of the motherwort extract on the mouse T lymphocyte activated by concanavalin A (conA) is indicated by the 3 H-thymidine intrusion method. It has a strong proliferative effect, and its effect is 5 to 8 times that of conA alone, indicating that it can enhance the cellular immune function of the body.
  • conA concanavalin A
  • the M-like action of the drug of the present invention increases the secretion of the liver gland, improves and strengthens the liver function, promotes its detoxification, metabolism, biotransformation speed and intensity, improves blood quality, blood circulation, and reduces portal hypertension and liver.
  • Treatment of glaucoma, cataract, fundus hemorrhage, tinnitus, deafness, hair loss Thirty-six patients with glaucoma were treated with oral administration of the drug of the invention for 15 days, 33 patients were markedly effective, 3 patients were effective, and 0 patients without hypotension, with an effective rate of 100%. There were 30 cases of cataract, 11 cases recovered, 16 cases improved symptoms, and 3 cases were ineffective.
  • the treatment of 13 patients with fundus hemorrhage can basically eliminate the symptoms in about 20 days.
  • the neuromodulation effect of the medicament of the present invention can have a significant therapeutic effect on functional tinnitus and deafness, stimulation of cholinergic nerves, improvement of sensitivity of the auditory nerve in the vestibular volute, and improvement of auditory function.
  • functional tinnitus and deafness stimulation of cholinergic nerves
  • improvement of sensitivity of the auditory nerve in the vestibular volute and improvement of auditory function.
  • the mechanism is that the skeletal muscle contraction of the occipital skeletal muscle, which is mainly based on the frontal muscle, causes the scalp tightness to increase the scalp tightness and enhance the utilization of local nutrients.
  • the enhanced synthesis of germinal substances and the enhanced function of the spleen are related to the enhanced function of the germinal center in the spleen.
  • nephritis uremia.
  • M-like effect, vasodilation makes the renal capillaries smooth, the glomerular filtration rate increases, and the diuretic effect of the bladder, so that the urine excretion is smooth, the edema subsides, the blood rheology index of the drug is improved, and the blood endotoxin is improved.
  • Reduced can effectively inhibit hematuria.
  • Gland secretion causes liver function to be strong, liver blood is improved, blood toxins that enter the kidney are reduced, thereby reducing the stimulation and destruction of toxic substances on the kidneys, while the sympathetic nerves are excited and stimulated. Recovers kidney function, protects nephron, corrects metabolic acidosis, and resists uremia.
  • Motherwort extract has a certain preventive effect on acute tubular necrosis (ATN) in the initial stage; it has protective effect on the kidney during the occurrence and development of acute renal failure caused by gentamicin; acute in rabbits caused by glycerol physiological saline Renal failure significantly increases renal cortical blood flow, improves renal function, reduces or restores renal tubular cell degeneration, turbid swelling and other pathological changes, with creatinine (cr), urea nitrogen (BCIN), filtered sodium excretion fraction (EFNC) Renal blood flow (RBF) and animal survival were used as indicators to demonstrate that the active ingredients of Leonurus extract have significant effects in the treatment of nephritis, uremia and renal failure.
  • ATN acute tubular necrosis
  • the M-like action of the medicament of the present invention can enhance the secretion of prostate function, stimulate the contraction of gland smooth muscle, inhibit the proliferation of prostate, hypertrophy, and improve and eliminate a series of symptoms such as urinary abnormality.
  • Motherwort extract has significant curative effect on prostatitis and benign prostatic hyperplasia and hypertrophy, which can reduce inflammation, inhibit fibrous tissue proliferation, increase local blood flow, significantly improve clinical symptoms of patients, and reduce the size of prostate. Improve a series of symptoms of urination.
  • test statistics showed that: 74 patients with diabetes were treated with the agent of the present invention, 74% of which achieved significant effect, 23% of which were basically effective, 3% of ineffective, and 97% of total effective rate.
  • sagging disorders are mostly caused by ligament relaxation or decreased muscle tension
  • Chinese medicine believes that the lack of gas in the system, caused by qi deficiency.
  • the M-like action and the N-like action of the medicament of the present invention can cause contraction of the gastric smooth muscle, contraction of the uterine smooth muscle, excitation of the superior and inferior phrenic nerves, restoration of normal neuromodulation function, and restoration of the organ tissue in situ.
  • the drug of the present invention forms a balance between hormones and functions secreted by the thyroid gland and the parathyroid gland through neuromodulation and humoral regulation, inhibits hyperthyroidism, supports hypotony, positively regulates, and acts dually to achieve high metabolism caused by thyroxine. Rate and exophthalmia symptoms, M-like effect makes the spleen smooth muscles excite and contract, inhibits spleen enlargement, through humoral regulation, blood rheology refers to The target is improved, the corresponding lymph fluid production is increased, the normal function of the spleen is improved and restored, the immune response ability of the spleen is improved, the platelet accumulation in the spleen and the autoimmune hemorrhagic reaction thus occurring are relieved. Clinical treatment of 70 cases of hyperthyroidism, 11 cases of splenomegaly, have achieved significant results.
  • the present invention has opened up a new application field by excavating new medical uses for the motherwort extracts such as oyster sauce, motherwort cream, motherwort syrup, motherwort granules, motherwort oral liquid, and motherwort capsules.
  • motherwort extracts such as oyster sauce, motherwort cream, motherwort syrup, motherwort granules, motherwort oral liquid, and motherwort capsules.
  • the active ingredients of motherwort extract, motherwort, motherwort, motherwort total alkaloid, motherwort A, and stachydrine are all acetylcholinesterase inhibitors, safe and non-toxic, and have strong pharmacological effects, indicating good medicinal prospects. .
  • the material of the invention has rich source and low cost, simple preparation process, and can be prepared into an oral dosage form, a syrup, an injection form, a tablet, a capsule type, an oil agent, a dropping pill, a granule, etc., and is convenient to use.
  • the medicament prepared by the substance of the invention has the remarkable use of the acetylcholinesterase inhibitor drug of the cholinergic medicine, and can treat and prevent Alzheimer's disease, rickets, schizophrenia, rheumatoid arthritis, psoriasis, vitiligo , goose palm wind, systemic lupus erythematosus, hypertension, cardiovascular and cerebrovascular diseases and other diseases.
  • the most important feature of the invention is that it not only makes the adjustment of the lesion more prominent, but also makes the overall adjustment close to perfection.
  • the substance of the invention can supplement a variety of amino acids, trace elements and vitamins required by the human body, and can be completely compatible with various oils and fats.
  • the effective active ingredients contained in the oil are not easily destroyed by high temperature, and have a flavor, Good taste, suitable for both medicine and food. Has eyesight, glory, suppresses tinnitus, reduces eye bags, reverses degenerative camel Back bending, inhibiting the relaxation and degenerative aging of organs such as the gastrointestinal, uterus and skeletal muscles, can positively regulate the body's functions, enhance the body's immunity, prevent the occurrence and development of many diseases, improve the sub-health state, prolong life and strengthen the body.
  • Acting on the oral cavity it can enhance the secretion of oral glands, fill the oral blood, keep the mouth moist and not dry, facilitate the exchange of substances in the periodontal matrix, enhance the timely supply of nutrients required by the teeth, strengthen the dentin, and accelerate The elimination of toxic substances in the roots of the teeth inhibits ulceration of the oral mucosa and reduces dental disease. It can also make the muscle smooth muscle of the gums excite and contract, stabilize the teeth and prevent the teeth from loosening. BRIEF DESCRIPTION OF THE DRAWINGS:
  • Figure 1 shows the percentage of inhibition of hAChE by water extract of Motherwort
  • Figure 2 shows the percentage inhibition effect of active ingredients of Motherwort on hAChE
  • Figure 3 shows the percentage of inhibition of hAChE and hBChE by motherwort base.
  • Figure 4 shows the percentage inhibition of AChE and BChE by motherwort.
  • Figure 5 shows the percentage inhibition of AChE and BChE by total alkaloids of Motherwort
  • Figure 6 shows the percentage inhibition of AChE and BChE by motherwort A.
  • Figure 7 shows the percentage inhibition of AChE and BChE by stachydrine.
  • motherwort 0.5 g corn starch 95. 5 g, magnesium stearate 4 g , all the components were uniformly mixed and made into 100 pieces. Each tablet contains 5 m g of motherwort base.
  • the capsule containing oyster sauce is prepared by pressing the motherwort ( ⁇ ) into oil, and filtering to obtain oyster oil, and each soft gelatin capsule is filled with lml oyster oil to prepare oyster oil capsule.
  • Motherwort sulphate (calculated as motherwort) 5 g , sucrose 100 g , citric acid 20 g , appropriate amount of essence, distilled water 5000 ml, made into 1000, take distilled water, the amount of prescription
  • Example 7 injection 0.5, 1, 1.5, 2.5, 5, 10, 20 mg / support
  • Motherwort sulfate (calculated as motherwort) 5 g , 5000 ml of water for injection, 1000 pieces. Dissolve the prescribed amount of motherwort sulphate in water for injection, add 0.3% of the needle to the activated carbon, stir for 30 minutes, decarbonize, sterilize and filter (0.22 rn microporous membrane), and dispense under sterile conditions. Melt seal, each 5ml, 100'C sterilization for 1 hour, check, that is.
  • Proportion of raw materials and auxiliary materials Take 5m g / branch as an example.
  • Leonurine sulfate (calculated by Leonurine) 5g, mannitol 95 g, 1,000 made lyophilized.
  • take the prescribed amount of motherwort sulphate and mannitol add appropriate amount of water for injection, control the pH value between 4.0 ⁇ 6.5, add water for injection to 1000ml, mix the hook, add 0.3% needle and stir with activated carbon for 30 minutes, decarbonize , sterile filtration (0.22 m microporous membrane), sub-packaged under aseptic conditions, each lml, freeze-dried into a white block or powder, that is.
  • Example 9 as a food product such as an edible oil additive
  • the ratio of raw materials and auxiliary materials On ⁇ lOnil, edible oil 5000ml, add oyster oil to the edible oil and stir to form a health-care edible oil.
  • Example 10 as a food product such as an edible oil additive
  • the ratio of raw materials and auxiliary materials On ⁇ lOnil, edible oil 300ml, add oyster oil to edible oil and stir to form a health-care edible oil.
  • Example 11 was made as a food product such as an edible oil additive
  • the ratio of raw materials and auxiliary materials 10ml of oyster sauce oil, 500ml of edible oil, adding oyster oil to edible oil for stirring, it is a health-care edible oil, which can be applied to the recovery of uterine function during pregnancy, accelerate the elimination of stagnation, and alleviate Pain after childbirth can also promote the elimination of pregnancy spots.
  • Example 12 as a rubbing cosmetic additive
  • Rubbing cosmetics such as moisturizing lotion, anti-wrinkle milk, mask, etc.
  • the active ingredient of motherwort extract, oyster oil or motherwort extract is added as an additive to the preparation of anti-wrinkle milk.
  • Preparation of raw materials and auxiliary materials 100 grams of oyster oil and 15 grams of sodium decyl sulfate are mixed, stirred and mixed for use. In addition, 10 g of vitamin C and 10 g of vitamin E and 0.1 g of ethyl p-hydroxybenzoate were added to 600 g of distilled water to dissolve. Finally, the two solutions prepared above were mixed, and emulsified by thorough stirring, and 0.1 g of the essence was added, and stirring was continued to obtain.
  • Example 13 as a washing-type commodity additive
  • washing daily necessities such as shampoo, soap, shower gel, etc.
  • the active ingredient of motherwort extract, oyster oil or motherwort extract is added as an additive to the preparation of shampoo.
  • each raw material ratio (1) Dissolve 3 g of calcium pantothenate in 70 g of water, stir until fully dissolved, and use. (2) 80 g of triethanolamine lauryl sulfate, 30 g of fatty acid diethanolamine, 0.2 g of formaldehyde (40% solution), and 3 g of hyaluronic acid were added to the solution prepared in the step (1), and stirred and uniformly mixed. (3) Dissolve 2 g of dragon grass oil and 1 g of stachydrine in ethanol, mix well, pour into the solution prepared in step (2), stir and mix to obtain the finished product.
  • Example 13 as an oral care-type daily necessities additive
  • Oral care daily necessities such as mouthwash, tooth powder, toothpaste, chewing gum, etc.
  • the active ingredient of the motherwort extract ⁇ ⁇ oil or motherwort extract is added as an additive to the preparation of the mouthwash.
  • the glass rod is mixed and evenly mixed to obtain the finished product.

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Abstract

L'invention concerne de nouvelles applications pour un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de Leonurus utilisé en tant que cholinomimétique. Les principes actifs de l'extrait sont la léonurinine, la léonurine, léonurines générales, la léonurine A, la cadabine, ou leurs mélanges ou des mélanges de leurs sels pharmaceutiquement acceptables ou des mélanges des deux, présentant des effets inhibiteurs sur l'acétylcholine estérase, et utilisé dans le traitement et la prévention de maladies telles que la démence présénile, la maladie d'Alzheimer, la maladie de Parkinson, l'hystérie, la schizophrénie, l'arthrite rhumatoïde, les lupus érythémateux systèmatiques, la myasthénie, l'amyotrophie progressive, des varicosités des membres inférieurs, la thromboangéite oblitérante, l'ecthyma, le psoriasis, le vitiligo, une maladie ansérine, l'hypertension, les maladies coronariennes, l'hyperlipidémie, les maladies cardiovasculaires et cérébrovasculaires, l'anémie aplastique, le purpura, la dissémination de l'agrégation intravasculaire, la ménoxénie et analogues.
PCT/CN2007/002456 2006-09-10 2007-08-15 Application d'un médicament inhibiteur d'acétylcholine estérase à base d'un extrait de leonurus utilisé en tant que cholinomimétique WO2008031322A1 (fr)

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CN114796181A (zh) * 2021-01-27 2022-07-29 中国海洋大学 益母草碱在制备用于防治非血管性痴呆或感染性中枢神经损伤的药物中的应用
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CN115317474A (zh) * 2021-05-10 2022-11-11 中国海洋大学 一种苯酰胍衍生物在用于制备预防和治疗神经系统疾病或心血管系统疾病的药物中的应用

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CN102727676B (zh) * 2012-07-10 2014-08-20 张加余 一种治疗过敏性紫癜的中药组合物及其制备方法和用途
CN106265622B (zh) * 2015-05-18 2019-12-03 复旦大学附属眼耳鼻喉科医院 益母草碱在制备视网膜视神经保护药物中的用途
CN105380945A (zh) * 2015-10-27 2016-03-09 江苏大学 益母草水苏碱在制备预防和治疗动脉粥样硬化的药物应用
CN105997975A (zh) * 2016-05-23 2016-10-12 南开大学 益母草碱在制备治疗血管性痴呆药物中的用途
CN111714484B (zh) * 2020-02-13 2022-01-25 王瑞 益母草碱用于预防急性肝损伤以及促进肝组织修复与再生
CN113440507A (zh) * 2020-03-26 2021-09-28 复旦大学 益母草碱在制备抗乙肝病毒药物中的用途
CN112022844A (zh) * 2020-09-02 2020-12-04 爱赫凯(广东)医疗科技有限公司 Scm-198在制备治疗银屑病药物中的应用
WO2022052016A1 (fr) * 2020-09-11 2022-03-17 Liu Hsuan Miao Compositions pharmaceutiques et leurs utilisations dans le traitement de la maladie de parkinson
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CN102134210A (zh) * 2010-01-22 2011-07-27 复旦大学 益母草碱衍生物及其制备方法
CN102134210B (zh) * 2010-01-22 2014-03-05 复旦大学 益母草碱衍生物及其制备方法
CN114796181A (zh) * 2021-01-27 2022-07-29 中国海洋大学 益母草碱在制备用于防治非血管性痴呆或感染性中枢神经损伤的药物中的应用
CN114796183A (zh) * 2021-01-27 2022-07-29 中国海洋大学 益母草碱在制备用于预防或治疗呼吸系统疾病的药物中的应用
CN114796183B (zh) * 2021-01-27 2024-01-09 中国海洋大学 益母草碱在制备用于预防或治疗呼吸系统疾病的药物中的应用
CN115317474A (zh) * 2021-05-10 2022-11-11 中国海洋大学 一种苯酰胍衍生物在用于制备预防和治疗神经系统疾病或心血管系统疾病的药物中的应用
CN113967206A (zh) * 2021-09-01 2022-01-25 中国农业大学 益母草碱在治疗多囊卵巢综合征的药物中的应用

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