CN114377005A - Application of eupatorium flavone in preparation of medicine for resisting hyperuricemia and gout - Google Patents

Application of eupatorium flavone in preparation of medicine for resisting hyperuricemia and gout Download PDF

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CN114377005A
CN114377005A CN202011129443.2A CN202011129443A CN114377005A CN 114377005 A CN114377005 A CN 114377005A CN 202011129443 A CN202011129443 A CN 202011129443A CN 114377005 A CN114377005 A CN 114377005A
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gout
hyperuricemia
uric acid
flavone
preparation
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杜冠华
周启蒙
杨海光
赵晓悦
宋俊科
张雯
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Institute of Materia Medica of CAMS
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    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Abstract

The invention belongs to the technical field of medicines, and discloses application of eupatorium flavone in preparation of anti-hyperuricemia and/or anti-gout drugs, wherein hyperuricemia comprises primary and secondary hyperuricemia and adult (male) with the uric acid concentration higher than 420 mu mol/L (female) 357 mu mol/L (determined by phosphotungstic acid reduction method) or more than 420 mu mol/L (determined by uricase-peroxidase coupling method) caused by various factors, and gout comprises primary gout and secondary gout. The invention discovers that the eupatorium adenophorum flavone can obviously reduce the activity of in-vitro xanthine oxidase and can effectively reduce the serum uric acid level of a hyperuricemia model mouse, which indicates that the eupatorium adenophorum flavone can be used for preparing medicines for treating hyperuricemia and/or gout and provides a safe, effective and economical active substance for preparing medicines for preventing and/or treating the diseases of hyperuricemia and/or gout.

Description

Application of eupatorium flavone in preparation of medicine for resisting hyperuricemia and gout
Technical Field
The invention relates to application of eupatorium adenophorum flavone in preparing a medicament, mainly relates to application of eupatorium adenophorum flavone in preparing a medicament for resisting hyperuricemia and gout, and belongs to the technical field of medicaments.
Background
Gout is arthropathy caused by crystal formation of mono-natriuretic urate, and is directly related to hyperuricemia caused by purine metabolic disorder and/or reduced uric acid excretion.
Hyperuricemia refers to the state that the uric acid concentration of adult plasma is higher than 420 mu mol/L in male blood and higher than 357 mu mol/L in female blood measured by a phosphotungstic acid reduction method, or higher than 420 mu mol/L in adult blood measured by a uricase-peroxidase coupling method, and is caused by the increase of uric acid production and (or) reduction of excretion in human body.
The treatment of hyperuricemia can be divided into drug therapy and non-drug therapy. Clinical research reports show that non-drug treatment can only reduce plasma uric acid levels by about 10-18%, and therefore is essential for drug treatment of hyperuricemia.
The therapeutic drugs for hyperuricemia can be divided into uric acid lowering drugs and anti-inflammatory drugs for controlling acute inflammatory attack. The uric acid lowering drugs can be classified into a xanthine oxidase inhibitor for reducing the production of uric acid, a uricosuric drug for increasing the excretion of uric acid and a uricase for decomposing uric acid according to the action mechanism. However, the existing medicines have adverse reactions with different degrees, such as hypersensitivity syndrome of allopurinol, so the traditional medicines are not ideal.
Herba Lycopi flavone (nepetin) flavonoid compound with molecular formula of C16H12O7CAS number: 520-11-6. The chemical structure is as follows:
Figure BDA0002734658190000011
at present, the effect of the eupatorium flavone in the anti-hyperuricemia and/or anti-gout drugs is not reported. The related patents which are inquired focus on the preparation, synthesis method and the like of eupatorium adenophorum flavone.
Disclosure of Invention
The invention aims to provide the application of eupatorium flavone in preparing anti-hyperuricemia and/or anti-gout drugs, thereby providing a solution with slight adverse reaction for reducing the concentration of uric acid in blood and treating gout.
Therefore, the invention provides the following technical scheme:
the invention provides application of eupatorium flavone in preparing a medicine for resisting hyperuricemia and/or gout.
Furthermore, the hyperuricemia comprises but is not limited to adults with uric acid concentration higher than 420 mu mol/L (male) caused by primary and secondary hyperuricemia and various factors, 357 mu mol/L (determined by phosphotungstic acid reduction method) or 420 mu mol/L (determined by uricase-peroxidase coupling method).
Further, the gout includes but is not limited to primary gout and secondary gout.
Furthermore, the eupatorium adenophorum flavone and pharmaceutically acceptable auxiliary materials can be prepared into anti-hyperuricemia and/or anti-gout drugs in various dosage forms according to a conventional preparation method.
The invention therefore also relates to pharmaceutical compositions containing the compounds according to the invention as active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The eupatorium adenophorum flavone can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary materials to prepare any dosage form for human or animal use. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of 0.1 to 99%.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the gastrointestinal or parenteral route, e.g., orally, intravenously, intramuscularly, subcutaneously, nasally, oromucosally, ocularly, pulmonary and respiratory, dermally, vaginally, rectally, etc.
The pharmaceutical composition dosage form comprises an oral preparation, an injection administration dosage form and a skin mucosa route administration dosage form.
The oral preparation comprises tablets, sustained-release preparations, capsules, controlled-release preparations, dripping pills and liquid preparations, and the injection administration dosage forms comprise intramuscular injection, intravenous injection and intravenous drip.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, carboxypropylmethylcellulose, ethylcellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, gallate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method. The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 100mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The invention has the beneficial effects that: the invention adopts an in-vitro xanthine oxidase inhibitor model to investigate the inhibitory action of eupatorium flavone on hyperuricemia and/or gout resisting medicines, in particular to xanthine oxidase, and the result shows that the in-vitro addition of 100 micrograms per milliliter of eupatorium flavone can obviously inhibit the xanthine oxidase activity, the inhibition rate is 45.3 +/-9.9%, the inhibition rate of 300 micrograms per milliliter is 76.9 +/-20.2%, the inhibition rate of 1 milligram per milliliter is 88.3 +/-5.3%, the experimental result of a hyperuricemia mouse model shows that the eupatorium flavone 5mg/kg and 20mg/kg can respectively reduce 58% and 40% of serum uric acid level, thus providing a potential safe and effective solution for the treatment, prevention and treatment of hyperuricemia and/or gout.
Drawings
FIG. 1 shows that eupatorium japonicum flavone in vitro experiment reduces xanthine oxidase activity.
Figure BDA0002734658190000042
FIG. 2 shows the effect of eupatorium japonicum flavone in eliminating free radicals in vitro.
Figure BDA0002734658190000043
FIG. 3 shows the uric acid-lowering effect of eupatorium japonicum flavone in mice.
Figure BDA0002734658190000044
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings.
EXAMPLE 1 herba Lycopi flavone reduces xanthine oxidase activity in vitro.
Experimental materials: herba Lycopi flavone is obtained from Chinese medical sciences institute of drug research center sample library, allopurinol, tert-butyl hydroquinone, xanthine oxidase, EDTA from Sigma Aldrich (Sigma-Aldrich, Germany). WST-1 was purchased from Dongren chemical technology (Shanghai) Inc.
Table 1. reaction system:
Figure BDA0002734658190000041
after the sample is loaded on a 384-well plate according to the reaction system in the table 1, the reaction system is continuously monitored for 20min, the absorption conditions of 295nm and 450nm are detected, and the change of the absorbance slope of 295nm is calculated. The slope of the 295nm absorption peak represents the rate of uric acid production and can be used for evaluating the xanthine oxidase activity; OD495 represents the amount of formazan generated by WST-1, and can be used for observing the reaction progress and the free radical generation amount.
As a result: the dose dependency of xanthine oxidase activity decreased after in vitro addition of eupatorium japonicum flavone (0.3,1, 3, 10, 30, 100, 300, 1000 μ g/ml), as shown in tables 2, 3 and fig. 1 and 2, suggesting that oral administration of eupatorium japonicum flavone can inhibit xanthine oxidase activity and further exert anti-hyperuricemia and/or anti-gout effects. IC50 (xanthine oxidase) was 150. mu.g/ml.
TABLE 2 in vitro assay for eupatorium japonicum flavone reduction of xanthine oxidase Activity
Figure BDA0002734658190000051
n＝3)。
Figure BDA0002734658190000052
TABLE 3 in vitro free radical scavenging effect of eupatorium japonicum flavone
Figure BDA0002734658190000053
n＝3)。
Figure BDA0002734658190000054
Experimental example 2 in vivo uric acid lowering effect of eupatorium japonicum flavone mice.
Experimental materials: the c57BL/6J mice were purchased from Wafunkang Biotech GmbH, Beijing. Potassium Oxazinate, benzbromarone, was purchased from Sigma Aldrich (Sigma-Aldrich, Germany). Herba Lycopi flavone is purchased from Shanghai-derived leaf Biotech limited. Sodium carboxymethylcellulose was purchased from national pharmaceutical group chemical reagents, ltd. The uric acid kit is purchased from Zhongsheng Bei Zhi Biotechnology GmbH.
Solution preparation: dissolving 0.5% sodium carboxymethylcellulose, boiling, cooling, and dissolving herba Lycopi flavone, Potassium Oxonate, and benzbromarone respectively to obtain suspension.
Grouping experiments: 18g mice were randomly assigned to normal control group, model group, benzbromarone group (20 mg. kg)-1Positive control), herba Lycopi flavone low and high dose group (5, 20mg/kg)-1) 5-8 in each group.
Except for the control group, 300mg kg of Potassium Oxonate is injected into the abdominal cavity every day-1The normal control group is injected with 0.5 percent sodium carboxymethylcellulose solution with the same amount every day, the continuous molding is carried out for 7 days, then the administration is carried out according to groups, the mice are killed after the administration is carried out for 7 days, the blood is taken from the venous plexus behind the eyes, the blood serum is taken after the standing is carried out for 2 hours, the speed is 4500rpm, the centrifugation is carried out for 15min at 4 ℃, and the serum uric acid level is measured by using a uric acid kit.
As a result: after the eupatorium adenophorum flavone (5, 20mg/kg) is orally taken by the model animals, the serum uric acid level can be respectively reduced by 58 percent and 40 percent, and other results are shown in a table 4 and a figure 3, which indicate that the eupatorium adenophorum flavone can play the role of resisting hyperuricemia and/or gout.
TABLE 4 influence of eupatorin on serum uric acid levels in hyperuricemia model mice: (
Figure BDA0002734658190000061
n＝5-8)。
Figure BDA0002734658190000062
Compared with the control group, ####': p <0.001, P <0.05, compared to model group: p < 0.001.
In conclusion, the invention adopts an in-vitro xanthine oxidase screening model to investigate the inhibitory action of eupatorium adenophorum flavone on hyperuricemia and/or gout resisting medicines, especially on xanthine oxidase, and the result shows that the in-vitro addition of eupatorium adenophorum flavone can obviously inhibit the xanthine oxidase activity and can obviously remove free radicals. Therefore, the eupatorium flavone has certain effect of resisting hyperuricemia and/or gout. The eupatorium flavone is taken as an active substance, is singly used or/and is combined with other compounds and/or extracts with pharmacological activity for compound use, and is prepared into anti-hyperuricemia and/or anti-gout drugs in various dosage forms according to the conventional preparation method in the field of pharmacy, or is prepared into compound preparations together with other uricosuric drugs and/or xanthine oxidase inhibitors and the like, so that the adverse reaction in the drug action is reduced under the condition of keeping the curative effect, and a safe and effective solution is provided for the treatment, prevention and treatment of hyperuricemia and/or gout.
Finally, while the present invention has been described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (7)

1. Application of 3', 4', 5, 7-tetrahydroxy-6-methoxyflavone shown as formula I or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and/or treating hyperuricemia or/and gout diseases
Figure FDA0002734658180000011
2. Use according to claim 1, characterized in that said hyperuricemia is primary, secondary or due to various factors, and is determined by phosphotungstic acid reduction to be a uric acid concentration in the blood of men higher than 420 μmol/L, a uric acid concentration in the blood of women higher than 357 μmol/L or a uricase-peroxidase coupling to be a uric acid concentration in the blood of adults higher than 420 μmol/L.
3. The use according to claim 1, wherein said gout is a primary gout induced by uric acid crystals in joints due to an increase in blood uric acid concentration and a secondary gout caused by various factors.
4. The use of a pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of hyperuricemia and/or gout comprising an effective amount of 3', 4', 5, 7-tetrahydroxy-6-methoxyflavone of claim 1, or a pharmaceutically acceptable salt thereof and optionally crystalline forms thereof, and a pharmaceutically acceptable carrier and other active ingredients
Figure FDA0002734658180000012
5. The use according to claim 4, characterized in that said pharmaceutical composition is selected from the group consisting of oral formulations, injectable formulations and formulations administered by the mucocutaneous route.
6. The use according to claim 5, wherein the oral preparation comprises a tablet, a sustained release preparation, a capsule, a controlled release preparation, a drop pill or a liquid preparation, and the administration form for injection comprises intramuscular injection, intravenous injection or intravenous drip.
7. The use according to claim 4, characterized in that the active principle involved in the pharmaceutical composition is derived from chemical substances capable of affecting the uric acid metabolism or the pathological course or manifestation of gout.
CN202011129443.2A 2020-10-21 2020-10-21 Application of eupatorium flavone in preparation of medicine for resisting hyperuricemia and gout Pending CN114377005A (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JIN KYU KIM 等: "Salvia plebeia Extract Inhibits Xanthine Oxidase Activity In Vitro and Reduces Serum Uric Acid in an Animal Model of Hyperuricemia", PLANTA MED., vol. 83, no. 17 *
刘佩 等: "车前草治疗痛风及高尿酸血症机制探讨", 辽宁中医药大学学报, vol. 22, no. 10, pages 174 *
李梦荣: "取代苯甲醛缩氨基硫脲及车前草中黄酮化合物抑制黄嘌呤氧化酶活性研究", 中国优秀硕士学位论文全文数据库工程科技Ⅰ辑, no. 12, pages 35 *

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