CN111084780A - Application of geraniin in preparing medicine for treating osteoporosis and fracture - Google Patents
Application of geraniin in preparing medicine for treating osteoporosis and fracture Download PDFInfo
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention provides application of geraniin in preparing a medicine for treating osteoporosis and fracture, belongs to the technical field of biological medicine, and can promote healing of the osteoporosis and fracture, improve bone density of osteoporosis, increase fracture strength, bone ash weight and bone calcium content and reduce the risk of reoccurrence of fracture. The invention also provides a medicine for treating osteoporosis complicated with fracture, which comprises geraniin; the medicine is administered in an amount of 1-200mg/kg geraniin per day, 1 or 2-4 times per day, and is administered in a manner of 9-12 weeks or more of intake.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of geraniin in preparation of a medicine for treating osteoporosis and fracture.
Background
Osteoporosis (OP) is a degenerative disease of the systemic bone tissue structure, and the elderly are predisposed to this disease. OP is a high risk factor of fracture, the incidence rate of OP combined fracture of the population over 60 years old is about 12.2 percent, the aging pace of the population in China is accelerated, the number of fracture cases caused by OP is increased year by year, the life health of the old is seriously threatened, and heavy burden is brought to families and society. Because OP is a progressive disease, the risk of re-fracture is high even after fracture healing if effective control therapy is not available. At present, the osteoporosis is mainly prevented and treated by the following aspects: preventing dietary calcium deficiency and vitamin D3 of special people in childhood, juvenile, gestation, etc., and controlling risk factors of morbidity; the early diagnosis of the disease is carried out through biochemical examination and bone imaging examination of serum bone-derived phosphatase, osteocalcin and the like; for patients with confirmed diagnosis, the patients are treated by changing living habits, supplementing sufficient calcium and vitamin D3 through diet control and applying medicines; the operation treatment is carried out on the patient with the damaged bone shape and structure. The existing treatment methods use bisphosphonates, estrogens, parathyroid hormone, calcitonin and vitamin D3 drugs singly or jointly, so that the treatment effects are better, but the defects of large toxic and side effects, inconvenient use of some drugs and the like exist, and the application of the drugs is limited to a certain extent.
Geraniin is extracted from Phyllanthus urinaria L (Euphorbiaceae), and has chemical structure shown in figure 1, and recent research shows that Geraniin has multiple pharmacological activities: (1) the in vivo and in vitro experiments show that the geraniin can eliminate oxygen free radicals, hydroxyl free radicals, superoxide free radicals and the like. (2) And (3) tumor resistance: geraniin can inhibit activity of transforming growth factor, etc., and can scare tumor migration, invasion, and decrease anti-apoptosis ability, inhibit tumor growth, and even accelerate tumor cell apoptosis. (3) Antiviral and antibacterial activity. The application of geraniin in treating osteoporosis complicated with fracture has not been reported.
Disclosure of Invention
The invention aims to provide application of geraniin in preparing a medicine for treating osteoporosis and fracture, wherein the geraniin can promote healing of the fracture, improve bone density of osteoporosis, increase fracture strength, bone ash weight and bone calcium content, and reduce the risk of reoccurrence of fracture.
The technical scheme adopted by the invention for realizing the purpose is as follows:
application of Geraniin in preparing medicine for treating osteoporosis complicated with fracture is provided. The geraniin has strong therapeutic effect on osteoporosis and combined fracture, can promote the union of combined fracture, improve the bone density of osteoporosis, improve fracture breaking force, bone ash weight and bone calcium content, reduce the risk of secondary fracture, and has small adverse reaction on the geraniin for treating osteoporosis and combined fracture patients.
According to one embodiment of the present invention, the geraniin is a geraniin monomer and/or a geraniin salt.
The invention also aims to provide a medicine for treating osteoporosis combined fracture, which comprises geraniin.
According to an embodiment of the invention, the medicament further comprises one or more agents selected from the group consisting of: vitamin C, vitamin A, vitamin D, vitamin B1, vitamin B2, vitamin B6, pantothenic acid, folic acid, calcium and magnesium. Preferably, the medicament further comprises vitamin D and calcium.
According to an embodiment of the invention, the medicament further comprises a pharmaceutically acceptable carrier and/or excipient and/or diluent.
According to an embodiment of the invention, the medicament is an oral composition.
Still another object of the present invention is to provide a method for treating osteoporosis complicated with fracture, which comprises the steps of: the medicament is applied in an amount of 1-200mg/kg geraniin per day. Preferably, administration is 1 or divided into 2-4 administrations per day.
According to one embodiment of the invention, the medicament is administered in a manner that results in an ingestion of 9-12 weeks or more.
The invention has the beneficial effects that: the geraniin has strong therapeutic effect on osteoporosis and combined fracture, can promote the union of combined fracture, improve the bone density of osteoporosis, improve fracture breaking force, bone ash weight and bone calcium content, reduce the risk of secondary fracture, and has small adverse reaction on the geraniin for treating osteoporosis and combined fracture patients.
Drawings
FIG. 1 is a chemical structural formula of Geraniin of the present invention;
FIG. 2 shows X plates of each group of animals in example 4 of the present invention.
Detailed Description
While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It is not intended to limit the invention to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
These examples are provided only for more specifically illustrating the present invention, and it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples according to the gist of the present invention.
The invention provides application of geraniin in preparing a medicine for treating osteoporosis and fracture. Osteoporosis is frequently found in the elderly, and the occurrence of osteoporotic fractures is associated with decreased bone density and mass. Once the osteoporotic fracture patient is fractured again, the patient usually needs to be kept in bed, and embolic diseases can be generated, even the patient dies. The geraniin has strong therapeutic effect on osteoporosis and combined fracture, can promote the union of combined fracture, improve the bone density of osteoporosis, improve fracture breaking force, bone ash weight and bone calcium content, reduce the risk of secondary fracture, and has small adverse reaction on the geraniin for treating osteoporosis and combined fracture patients.
In one embodiment of the present invention, the geraniin is a geraniin monomer or a geraniin salt.
In one embodiment of the present invention, the geraniin is derived from an active extract of Phyllanthus urinaria L, a plant of Euphorbiaceae.
In one embodiment of the present invention, the geraniin is obtained by the following method:
1) adding the phyllanthus urinaria powder into an extracting solution containing 0.3-1.5% of lactic acid, 20-25% of ammonium sulfate and 17-23% of ethanol according to the mass concentration of 1:10-20, extracting for 40-50min under the ultrasonic wave of 150 plus 180W, centrifuging for 5-12min at 8000 plus 15000r/min, standing and layering the supernatant in a separating funnel, and filtering through a 0.45 mu m microporous filter membrane to obtain the extracting solution; the geraniin is hydrolysable tannin, is extracted by a heating reflux method and is easily decomposed into gallic acid, hexahydroxy diphenyl dicarboxylic acid, ellagic acid, corilagin and corilagin, and the active ingredients in the plant materials can be accelerated to enter a solvent by utilizing strong vibration, high acceleration, strong cavitation effect, stirring effect and the like generated by ultrasonic waves, so that the extraction rate of the active ingredients is increased, the extraction time is shortened, and the influence of high temperature on the extracted ingredients can be avoided; meanwhile, the extracting solution can better destroy the increase of the acting force of the phenolic substances and the matrix under the lower ethanol concentration, is beneficial to the dissolution of the phenolic substances, has strong selectivity on the phenolic substances, is beneficial to the extraction of the phenolic substances in the phyllanthus urinaria powder, and ensures that the extraction rate of the phenolic substances in the phyllanthus urinaria powder can reach at least 8.4 percent;
2) preparing a solvent system from petroleum ether, ethyl acetate, methanol, ammonium citrate and water according to a volume ratio of 0.3-0.7:5-15:0.1-0.3:0.04-0.0.08:18-25, placing the solvent system into a separating funnel, shaking uniformly, standing for layering, after balancing for 1-4h, separating an upper phase from a lower phase, taking the upper phase as a stationary phase and the lower phase as a mobile phase;
3) filling the fixed phase into a column of a high-speed counter-current chromatograph at the flow rate of 10-15mL/min, then operating a main machine of the high-speed counter-current chromatograph in the forward direction at the rotating speed of 700 plus 800r/min, simultaneously pumping the mobile phase at the flow rate of 0.5-1.5mL/min, when the mobile phase begins to flow out of the chromatographic column, injecting an extracting solution which is dissolved into the mobile phase according to the mass concentration of 1-10mg/mL through an injection valve, entering a sample separation state, simultaneously setting the ultraviolet detection wavelength to be 280nm, and then collecting the geraniin fraction according to the ultraviolet spectrogram of a detector. The high-speed countercurrent chromatography (HSCCC) is a better method for separating compounds which are similar in property and easy to denature at present, the distribution coefficient of the geraniin in the solvent system used in the embodiment is proper, the geraniin can be better separated, the purity and the recovery rate of the geraniin fraction are improved, and the purity of the geraniin fraction can reach at least 94% and the recovery rate can reach at least 90% through HPLC detection. Further purifying the geraniin fraction to obtain more than 99% of pure geraniin.
The invention also provides application of the geraniin and the myricetin in preparing a medicament for treating osteoporosis complicated with fracture. Wherein the weight ratio of the geraniin to the myricetin is 1: 0.05-0.3. The geraniin and myricetin are matched to have a synergistic enhancement effect, can be used for synergistically treating osteoporosis and combined fracture symptoms of ovariectomized Japanese long-ear white rabbits, synergistically promoting the healing of combined fracture, synergistically improving bone density, fracture breaking force, bone ash weight and bone calcium content, and greatly reducing the risk of secondary fracture.
The invention also provides application of the geraniin and the chlorogenic acid in preparing the medicine for treating osteoporosis and fracture. Wherein the weight ratio of the geraniin to the chlorogenic acid is 1: 0.1-0.25. The compatibility of the geraniin and the chlorogenic acid shows a synergistic enhancement effect, can synergistically treat osteoporosis and combined fracture symptoms of the ovariectomized Japanese long-ear white rabbit, synergistically promote the healing of combined fracture, synergistically improve the bone density, the fracture strength, the bone ash weight and the bone calcium content, and greatly reduce the risk of secondary fracture.
The invention also provides a medicine for treating osteoporosis combined fracture, which comprises geraniin and/or myricetin, or comprises geraniin and/or chlorogenic acid.
In one embodiment of the present invention, the medicament further comprises one or more agents selected from the group consisting of: vitamin C, vitamin A, vitamin D, vitamin B1, vitamin B2, vitamin B6, pantothenic acid, folic acid, calcium lactate, calcium and magnesium. Preferably, the medicament further comprises vitamin D and calcium lactate.
In one embodiment of the present invention, the medicament further comprises a pharmaceutically acceptable carrier and/or excipient and/or diluent. Among the carriers, excipients, and diluents that may be included are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
In one embodiment of the invention, the medicament is an oral composition. The medicine is in the form of powder, pill, granule, tablet, capsule, suspension, liquid, emulsion or syrup. The solid drug is produced by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. Furthermore, in addition to simple excipients, lubricants such as magnesium stearate, talc, and the like are also used. The liquid medicine may contain various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc., in addition to conventional simple diluents such as water and liquid paraffin.
The invention also provides a use method of the medicine.
The invention also provides a use method of the medicine, wherein the medicine is applied according to the amount of 1-200mg/kg of geraniin per day. Preferably, administration is 1 or divided into 2-4 administrations per day.
In one embodiment of the invention, the drug is administered by ingestion for 9-12 weeks or more.
The present invention is further described in detail with reference to the following examples:
example 1:
the geraniin is obtained by the following method:
1) adding cacumen Securinegae Suffruticosae powder into extractive solution containing 0.8% lactic acid, 22% ammonium sulfate and 19% ethanol at a ratio of 1:14, extracting under 160W ultrasonic wave for 45min, centrifuging at 10000r/min for 8min, standing supernatant in separating funnel for layering, and filtering with 0.45 μm microporous membrane to obtain extractive solution with phenolic substance extraction rate of 8.83%;
2) preparing a solvent system from petroleum ether, ethyl acetate, methanol, ammonium citrate and water according to a volume ratio of 0.5:10:0.2:0.05:20, placing the solvent system in a separating funnel, shaking uniformly, standing for layering, after balancing for 2 hours, separating an upper phase from a lower phase, taking the upper phase as a stationary phase, and taking the lower phase as a mobile phase;
3) filling a column of a high-speed counter-current chromatograph with the stationary phase at a flow rate of 12mL/min, then operating a main machine of the high-speed counter-current chromatograph in a forward direction at a rotating speed of 750r/min, simultaneously pumping the mobile phase at a flow rate of 1.0mL/min, when the mobile phase begins to flow out of the chromatographic column, injecting an extracting solution dissolved in the mobile phase at a mass concentration of 3mg/mL through an injection valve, entering a sample separation state, simultaneously setting an ultraviolet detection wavelength to be 280nm, and then collecting geraniin fraction according to an ultraviolet spectrogram of a detector. HPLC detection shows that the purity of the geraniin fraction is 95.2%, and the recovery rate is 90.8%.
Example 2:
the geraniin is obtained by the following method:
1) adding cacumen Securinegae Suffruticosae powder into extractive solution containing 0.8% lactic acid, 22% ammonium sulfate and 19% ethanol at a ratio of 1:14, extracting under 160W ultrasonic wave for 45min, centrifuging at 10000r/min for 8min, standing supernatant in separating funnel for layering, and filtering with 0.45 μm microporous membrane to obtain extractive solution with phenolic substance extraction rate of at least 5.44%;
2) preparing a solvent system from petroleum ether, ethyl acetate, methanol and water according to the volume ratio of 0.5:10:0.2:20, placing the solvent system into a separating funnel, shaking uniformly, standing for layering, after balancing for 2 hours, separating an upper phase from a lower phase, taking the upper phase as a stationary phase, and taking the lower phase as a mobile phase;
3) filling a column of a high-speed counter-current chromatograph with the stationary phase at a flow rate of 12mL/min, then operating a main machine of the high-speed counter-current chromatograph in a forward direction at a rotating speed of 750r/min, simultaneously pumping the mobile phase at a flow rate of 1.0mL/min, when the mobile phase begins to flow out of the chromatographic column, injecting an extracting solution dissolved in the mobile phase at a mass concentration of 3mg/mL through an injection valve, entering a sample separation state, simultaneously setting an ultraviolet detection wavelength to be 280nm, and then collecting geraniin fraction according to an ultraviolet spectrogram of a detector.
Comparing example 1 with example 2, it is clear that the extraction rate of polyphenol is higher in example 1 than in example 2, which shows that the extraction rate of polyphenol can be improved by the extract liquid in example 1.
Example 3:
the geraniin is obtained by the following method:
1) adding cacumen Securinegae Suffruticosae powder into extractive solution containing 0.8% lactic acid, 22% ammonium sulfate and 19% ethanol at a ratio of 1:14, extracting under 160W ultrasonic wave for 45min, centrifuging at 10000r/min for 8min, standing supernatant in separating funnel for layering, and filtering with 0.45 μm microporous membrane to obtain extractive solution;
2) preparing a solvent system from petroleum ether, ethyl acetate, methanol and water according to the volume ratio of 0.5:10:0.2:20, placing the solvent system into a separating funnel, shaking uniformly, standing for layering, after balancing for 2 hours, separating an upper phase from a lower phase, taking the upper phase as a stationary phase, and taking the lower phase as a mobile phase;
3) filling a column of a high-speed counter-current chromatograph with the stationary phase at a flow rate of 12mL/min, then operating a main machine of the high-speed counter-current chromatograph in a forward direction at a rotating speed of 750r/min, simultaneously pumping the mobile phase at a flow rate of 1.0mL/min, when the mobile phase begins to flow out of the chromatographic column, injecting an extracting solution dissolved in the mobile phase at a mass concentration of 3mg/mL through an injection valve, entering a sample separation state, simultaneously setting an ultraviolet detection wavelength to be 280nm, and then collecting geraniin fraction according to an ultraviolet spectrogram of a detector. HPLC detection shows that the purity of the geraniin fraction is 89.7%, and the recovery rate is 82.5%.
Comparing example 1 with example 2, it can be seen that the distribution coefficient of geraniin in the solvent system used in example 1 is appropriate, so that the geraniin can be well separated, and the purity and recovery rate of the geraniin fraction can be improved.
Example 4:
influence of geraniin on bone density and fracture healing of osteoporosis and fracture-complicated Japanese Long-ear white rabbit
1. Experimental animals:
healthy and clean grade female Japanese long-ear white rabbits, weighing 2-2.5kg, were provided by the laboratory animal center of Kunming medical college [ laboratory animal experimental production license number: SCXK (Dian.) 2015 + 0002 ]. Feeding conditions are as follows: the temperature is 22 +/-5 ℃, the relative temperature is 60-70%, a single cage is used for feeding only one single cage, the complete beverage is fed, the feeding is carried out once a day, and the automatic drinking device is used for freely drinking water.
2. Molding die
2.1 replication of the osteoporosis model: an experimental rabbit bilateral ovarian ablation replication osteoporosis model is used for simulating human postmenopausal osteoporosis. After the experimental rabbits were adaptively raised for three weeks, animals were anesthetized by 1ml/kg body weight with 3% sodium pentobarbital by otic intravenous injection, fixed in the supine position, 3cm unhaired along each side of the ventral midline under 2/3, the operative area was sterilized with iodophor and deiodinated with ethanol twice, and the skin and peritoneum were incised along the ventral midline with a 3cm long incision. The operator stretches into the front of the pelvis to find the uterus, finds the uterine horns on two sides forwards along the uterus and pulls the uterine horns to the wound, and then lifts the oviduct along the uterine horns to find the ovary. The suspensory ligament of the ovary was isolated blunt and the ovary was lifted out of the abdominal wall incision. A small hole is formed on the ovary mesentery close to the ovary blood vessel, 3 hemostats are used for clamping the ovary and the surrounding tissues, one of the hemostats is close to the ovary, the other two hemostats are far away from the ovary, then the ovary mesentery and the blood vessel are cut off by ligating at the position 2mm outside the far-end hemostat of the ovary by using a suture, and the ovary is removed. Observing whether bleeding exists or not, and if bleeding exists, performing second ligation at the position just clamped to stop bleeding; the bird nest is returned to the abdominal cavity without bleeding. The normal control group did not remove the ovary, only removed part of the adipose tissue around the ovary, and the rest of the surgery methods were consistent. Closing the incision after removing both ovaries, and suturing peritoneum and abdominal wall muscles by using a round needle and a No. 7 surgical thread; the skin was sutured with a triangular needle and 7 gauge thread. After the iodophor is disinfected, the operation is finished, the reaction of animals is observed after the operation, and if infection occurs, ceftriaxone can be injected into the abdominal cavity to resist the infection.
2.2 fracture model replication: the experimental animals are anesthetized by injecting 3% sodium pentobarbital into ear vein according to 1ml/kg body weight, fixed in a lying position, the fur of the left front limb wound bone part is removed, the skin is cut, the wound bone is separated, a part of the wound bone is removed by using a bone wire saw to form the wound bone fracture with the width of 2mm and the depth of 1/2 diameters, and the osteoporosis and fracture animal model is formed. The incision was closed and the periosteum and skin were sutured separately. The model group and the treatment group were cut open the skin and made fracture models, and the normal control group was cut open only the skin and isolated the surrounding bone without making fracture.
3. Experimental grouping and treatment
30 Japanese Long-ear white rabbits were randomly divided into 3 groups of normal control group, osteoporosis-complicated fracture model group, osteoporosis-complicated fracture +10 mg/kg-d Geraniin treatment group, and each group had 10 rabbits. The osteoporosis model and the 10 mg/kg-d geraniin treatment group animals are copied by a method of removing ovaries by surgery, and fat tissues around the ovaries are removed by surgery in a normal control group for pseudo surgery. 3 months after the osteoporosis model is copied, when the animals without ovaries have osteoporosis and the bone density is obviously different from the normal contrast, the fracture model copying is carried out on the 10mg/kg d geraniin model group and the treatment group to form an osteoporosis and fracture model. Immediately after operation, the treatment group is treated by administering geraniin 10mg/kg every day, and after feeding for 10 weeks, serum biochemical index detection, X-ray detection and bone recovery index detection are carried out.
4. Analysis of results
4.1 serum Biochemical index detection
Serum calcium, phosphorus, alkaline phosphatase are common indicators for assessing bone formation and bone turnover. The serum alkaline phosphatase, serum calcium and phosphorus concentrations are measured by a full-automatic biochemical analyzer, the results are shown in table 1, compared with a sham operation group, the serum alkaline phosphatase, serum calcium and serum phosphorus levels of a model control group and a treatment group are increased, the increase of the treatment group is obvious, and the intervention of the geraniin has a promotion effect on the quality of fracture healing.
TABLE 1 Biochemical indexes of serum of osteoporosis and fracture groups
| Group of | Alkaline phosphatase (U/L) | Serum calcium (mmol/L) | Serum phosphorus (mmol/L) |
| Normal control group | 81.94±7.19 | 2.70±0.21 | 1.57±0.15 |
| Model control group | 83.08±7.03 | 2.23±0.18 | 2.00±0.14 |
| Treatment group | 83.76±8.47ab | 2.43±0.26ab | 2.07±0.14ab |
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
4.2X-ray detection
The fracture healing condition of osteoporosis complicated fracture rat is observed by X plain film (as shown in figure 2, wherein A is normal control group, B is model control group, and C is geraniin treatment group), and as can be seen from figure 2, after 10 weeks of treatment of 10 mg/kg. d geraniin, the fracture healing of the treatment group is obvious, the fracture healing score is obviously increased, but fracture lines can still be seen. And the fracture healing score is carried out according to the scoring table shown in the table 2, the scoring result is shown in the table 3, and it can be seen that after 10 weeks of treatment of 10 mg/kg. d geraniin, the fracture healing score of the osteoporosis complicated fracture rat is higher, and compared with the model control group, the difference has statistical significance.
TABLE 2 fracture heal score-table
| X-ray representation | Value of credit |
| No callus shadow was found on the |
0 |
| Callus shadow can be seen on the X-ray film, and the fracture line is relatively fuzzy | 1 |
| With obvious callus growth and obvious blurring of fracture lines | 2 |
| Has abundant callus growth and nearly disappeared fracture line | 3 |
| The fracture line disappears, is completely connected and approaches ossification | 4 |
TABLE 3 osteoporosis with fracture rat fracture healing score
| Group of | Fracture healing score |
| |
0 |
| Model control group | 3.160±0.259 |
| Treatment group | 4.390±0.197b |
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
4.3 bone recovery index detection
The bone density is an important index reflecting the bone strength, and is measured by a dual-energy X-ray bone density measuring instrument; the fracture force of the fracture is measured by a bone strength meter in a three-point fracture square way; the weight of the bone ash is measured after ashing for 2 hours at 800 ℃ by adopting a muffle furnace; the calcium and magnesium concentration in the supernatant is determined after the bone ash is dissolved by hydrochloric acid, and the corresponding calcium and magnesium content in the bone is calculated. The bone recovery indexes of animals in each group of osteoporosis and combined fracture are shown in table 4, after 10-week treatment of 10 mg/kg. d geraniin, the fracture force of the left radius, the weight of the bone ash of the left radius, the bone calcium content and the bone density are obviously increased, and compared with a model control group, the difference has statistical significance, which shows that the bone density is increased after the geraniin is dried.
TABLE 4 osteoporosis recovery index for animal groups with fracture
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
Example 5:
effect of Geraniin and myricetin on bone density and fracture healing of osteoporosis and fracture-complicated Japanese Long-ear white rabbit
1. Experimental animals: as in example 4.
2. Molding: as in example 4.
3. Experimental grouping and treatment
Japanese Long-ear white rabbits were randomly divided into 5 groups of a normal control group, an osteoporosis-complicated fracture model group, an osteoporosis-complicated fracture +10 mg/kg-d Geraniin treatment group 1, an osteoporosis-complicated fracture +2.0 mg/kg-d myricetin treatment group 2, and an osteoporosis-complicated fracture +10 mg/kg-d Geraniin +2.0 mg/kg-d myricetin treatment group 3, each group consisting of 10 rabbits. The osteoporosis model, treatment 1 group, treatment 2 group and treatment 3 group animals adopt a method of removing ovaries by surgery to duplicate the osteoporosis model, and fat tissues around the ovaries are removed by surgery in a normal control group to carry out a pseudo surgery. 3 months after the osteoporosis model is copied, when the animals without ovaries have osteoporosis and the bone density is obviously different from the normal contrast, the fracture model copying is carried out on the 10mg/kg d geraniin model group and the treatment group to form an osteoporosis and fracture model. Immediately after the operation, the treatment of 1 group of the patients starts to be treated by 10mg/kg of geraniin every day, the treatment of 2 groups of the patients starts to be treated by 2.0mg/kg of d-myricetin every day, the treatment of 3 groups of the patients starts to be treated by 10mg/kg of geraniin and 2.0mg/kg of d-myricetin every day, and the serum biochemical index detection, the X-ray detection and the bone recovery index detection are carried out after the patients are fed for 10 weeks.
4. Compatibility calculation method
Calculating the q value according to the formula of King, wherein q is equal to EA+B/(EA+EB-EA×EB) And is used for judging whether the effect of the two medicines after being used in a matching way is better than that of single administration. If q is<0.55, the two medicines have obvious antagonism; q is not less than 0.55<0.85, the two medicines have antagonistic action; q is not less than 0.85<1.15, the two medicines have the functions of simple addition; q is not less than 1.15<20, the two medicines have synergistic effect; q is not less than20, the effects of the two medicines are obviously enhanced.
5. Analysis of results
5.1 serum Biochemical index detection
The results of the measurement of serum alkaline phosphatase, serum calcium and phosphorus concentrations are shown in table 5, and compared with the model control group, the serum alkaline phosphatase, serum calcium and serum phosphorus levels in the 1 treatment group and the 3 treatment groups are increased obviously, which shows that the intervention of geraniin has a promoting effect on the quality of fracture healing and the effect of the combined medicine of geraniin and myricetin in the 3 treatment groups is better.
TABLE 5 serum biochemical indices of osteoporosis with fracture
| Group of | Alkaline phosphatase (U/L) | Serum calcium (mmol/L) | Serum phosphorus (mmol/L) |
| Normal control group | 81.94±7.19 | 2.70±0.21 | 1.57±0.15 |
| Model control group | 83.08±7.03 | 2.23±0.18 | 2.00±0.14 |
| Treatment 1 group | 83.76±8.47ab | 2.43±0.26ab | 2.07±0.14ab |
| Treatment of 2 groups | 82.24±5.35ab | 2.25±0.19ab | 1.93±0.12ab |
| Treatment of 3 groups | 86.55±8.47ab | 2.56±0.26ab | 2.24±0.14ab |
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
5.2X-ray detection
The fracture healing condition of the osteoporosis-complicated fracture rat is observed by adopting an X plain film, the fracture healing scoring is carried out according to the scoring table shown in table 2, the scoring result is shown in table 6, and after 10 weeks of treatment, compared with a model control group, the fracture healing scoring of the osteoporosis-complicated fracture rat of 1 group, 2 groups and 3 groups is higher and the effect of 3 groups is optimal, which shows that the compatibility of geraniin and myricetin in the 3 groups can synergistically treat osteoporosis-complicated fracture symptoms of the ovary-removed Japanese Long-ear white rabbit, and synergistically promote the union of the complicated fracture.
TABLE 6 osteoporosis Co-fracture rat fracture healing score
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
4.3 bone recovery index detection
After 10 weeks of treatment, the bone recovery indexes of animals with osteoporosis and fracture in each group are shown in table 7, compared with a model control group, the bone density of the radius in the treatment 1 group, the treatment 2 group and the treatment 3 group is respectively increased by 16.91%, 4.83% and 26.57%, according to a King's formula, q is 26.57%/(16.91% + 4.83% -16.91% × 4.83%) is 1.27 (shown in table 7), and q is more than or equal to 1.15 and less than or equal to 20, which indicates that the compatibility of geraniin and myricetin has a synergistic effect on increasing the bone density of the radius. Meanwhile, as can be seen from table 7, compared with the model control group, the left radius fracture force, the left radius bone ash weight, the bone calcium content and the L3 lumbar vertebrae density of the radius of the treatment groups 1, 2 and 3 are obviously increased, and q of the left radius fracture force, the left radius bone ash weight, the bone calcium content and the L3 lumbar vertebrae density of the treatment groups 3 are respectively 1.20, 1.65, 1.29 and 2.10 and are consistent with q being more than or equal to 1.15 and less than 20, which indicates that the compatibility of geraniin and myricetin in the treatment groups 3 is synergistic, the bone density, the bone fracture strength, the bone ash weight and the bone calcium content are synergistically increased, and the risk of bone fracture reoccurrence is greatly reduced.
TABLE 7 osteoporosis recovery index for animals with osteoporosis and fracture
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
Example 6:
effect of Geraniin and chlorogenic acid on bone density and fracture healing of osteoporosis and fracture-complicated Japanese Long-ear white rabbit
1. Experimental animals: as in example 4.
2. Molding: as in example 4.
3. Experimental grouping and treatment
Japanese Long-ear white rabbits were randomly divided into 5 groups of a normal control group, an osteoporosis combined fracture model group, an osteoporosis combined fracture +10 mg/kg-d geraniin treatment group 1, an osteoporosis combined fracture +1.8 mg/kg-d chlorogenic acid treatment group 2, and an osteoporosis combined fracture +10 mg/kg-d geraniin +1.8 mg/kg-d chlorogenic acid treatment group 3, each group consisting of 10 rabbits. The osteoporosis model, treatment 1 group, treatment 2 group and treatment 3 group animals adopt a method of removing ovaries by surgery to duplicate the osteoporosis model, and fat tissues around the ovaries are removed by surgery in a normal control group to carry out a pseudo surgery. 3 months after the osteoporosis model is copied, when the animals without ovaries have osteoporosis and the bone density is obviously different from the normal contrast, the fracture model copying is carried out on the 10mg/kg d geraniin model group and the treatment group to form an osteoporosis and fracture model. Immediately after operation, the treatment of 1 group is started to be treated by 10mg/kg geraniin every day, the treatment of 2 groups is started to be treated by 1.8mg/kg d chlorogenic acid every day, the treatment of 3 groups is started to be treated by 10mg/kg geraniin and 1.8mg/kg d chlorogenic acid every day, and after 10 weeks, the biochemical index detection, the X-ray detection and the bone restoration index detection of the blood serum are carried out.
4. The compatibility calculation method comprises the following steps: as in example 5.
5. Analysis of results
5.1 serum Biochemical index detection
The results of the measurement of the serum alkaline phosphatase, the serum calcium and the serum phosphorus concentrations are shown in table 8, compared with the model control group, the serum alkaline phosphatase, the serum calcium and the serum phosphorus levels in the treatment 1 group and the treatment 3 groups are increased obviously, which shows that the intervention of the geraniin has a promoting effect on the quality of fracture healing and the effect of the combined medicine of the geraniin and the chlorogenic acid in the treatment 3 groups is better.
TABLE 8 serum biochemical index of osteoporosis and fracture
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
5.2X-ray detection
The fracture healing condition of the osteoporosis-complicated fracture rat is observed by adopting an X plain film, the fracture healing scoring is carried out according to the scoring table shown in table 2, the scoring result is shown in table 9, and after 10 weeks of treatment, compared with a model control group, the fracture healing scoring of the osteoporosis-complicated fracture rat in 1 group, 2 groups and 3 groups is higher and the effect of 3 groups is optimal, which shows that the compatibility of geraniin and chlorogenic acid in the 3 groups can synergistically treat osteoporosis-complicated fracture symptoms of the ovary-removed Japanese long-ear white rabbit, and synergistically promote the union of the complicated fracture.
TABLE 9 osteoporosis Co-fracture rat fracture healing score
| Group of | Fracture healing score |
| |
0 |
| Model control group | 3.160±0.259 |
| Treatment 1 group | 4.390±0.197b |
| Treatment of 2 groups | 3.243±0.156b |
| Treatment of 3 groups | 4.690±0.163b |
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
4.3 bone recovery index detection
After 10 weeks of treatment, the bone recovery indexes of animals in each group of osteoporosis-complicated fracture are shown in table 10, compared with a model control group, the bone density of the radius in the treatment 1 group, the treatment 2 group and the treatment 3 group is respectively increased by 16.91%, 2.41% and 24.25%, according to a King's formula, q is 24.25%/(16.91% + 2.41% -16.91% × 2.41%) is 1.28 (shown in table 10), and the result accords with that q is more than or equal to 1.15 and less than or equal to 20, which indicates that the compatibility of the geraniin and the chlorogenic acid has a synergistic effect on increasing the bone density of the radius. Meanwhile, as can be seen from table 10, compared with the model control group, the left radius fracture force, the left radius bone ash weight, the bone calcium content and the L3 lumbar vertebrae density of the radius of the treatment groups 1, 2 and 3 are obviously increased, and q of the left radius fracture force, the left radius bone ash weight, the bone calcium content and the L3 lumbar vertebrae density of the treatment groups 3 are respectively 1.25, 1.88, 1.62 and 1.63 and are all consistent with q being more than or equal to 1.15 and less than or equal to 20, which indicates that the compatibility of geraniin and chlorogenic acid in the treatment groups 3 is synergistic, the bone density, the bone fracture force, the bone calcium content are synergistically increased, and the risk of bone fracture reoccurrence is greatly reduced.
TABLE 10 osteoporosis recovery index for animal groups with fracture
Note: a represents the statistical difference from the normal control group (P <0.05), and b represents the statistical difference from the model control group (P < 0.05).
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (8)
1. Application of Geraniin in preparing medicine for treating osteoporosis complicated with fracture is provided.
2. Use according to claim 1, characterized in that: the Geraniin is Geraniin monomer and/or Geraniin salt.
3. A medicament for treating osteoporosis complicated with fracture comprising the geraniin of claim 1.
4. The medicament of claim 3, wherein: the medicament further comprises one or more agents selected from the group consisting of: vitamin C, vitamin A, vitamin D, vitamin B1, vitamin B2, vitamin B6, pantothenic acid, folic acid, calcium and magnesium.
5. The medicament of claim 3, wherein: the medicament further comprises a pharmaceutically acceptable carrier and/or excipient and/or diluent.
6. The medicament of claim 3, wherein: the medicament is an oral composition.
7. The use of the medicament of claim 3, wherein: the medicament is applied in an amount of 1-200mg/kg geraniin per day. Preferably, administration is 1 or divided into 2-4 administrations per day.
8. Use according to claim 7, characterized in that: the medicament is administered in a manner that results in ingestion for 9-12 weeks or more.
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