CN104547055A - Application of rhizoma corydalis in inhibiting advanced tumor pain - Google Patents
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Abstract
The invention provides application of rhizoma corydalis in inhibiting advanced tumor pain.
Description
Technical field
The present invention relates to the medical usage of active component in a kind of Chinese herbal medicine of extraction, be specifically related to the application of Rhizoma Corydalis in the medicine of antitumor pain in late period processed.
Background technology
Pain is the most common and insufferable a kind of symptom of tumor patient, is also one of symptom the most rambunctious simultaneously.International pain association definition pain is the impression in a kind of sensation beastly and emotion, with or potential tissue injury.According to World Health Organization (WHO) (WHO) statistics, the whole world about has 1,000 ten thousand new cancer patients every year, and wherein the cancer patient of 50% has cancerous pain symptom, and the patient with advanced cancer of 70% take pain as cardinal symptom.Cancer pain its reason that makes internal disorder or usurp is the pain caused due to cancerous protuberance itself and the factor relevant with cancerous protuberance.Cancer pain can be divided into original site cancer pain and metastasis site cancer pain, and mainly cancerous cell is to nociceptive pain caused after tissue infiltration.Along with the diffusion of cancerous tissue, the many persistence of cancer pain exists, and along with the prolongation of the course of disease and the development of the state of an illness be Progressive symmetric erythrokeratodermia or intermittent aggravation, often occur breaking out bitterly, night is particularly serious.
Cancerous pain is as the common sympton of Advanced cancers, and outer because experience pathogen, evil poison, interior because internal organs store, poison, feelings will are smooth, pica and positive QI-insufficiency.Studying carefully its main cause is deficiency of vital QI; cause in exopathogen, pyretic toxicity etc. and invade and expectorant, tired mutual knot, " poison " " addiction " causes meridians to be jammed for the basic pathogenesis of cancer pain, and strongly fragrant in cancer poison is the key of pathogenesis; according to the position of tumor invasion and the physiological and pathological feature of affiliated internal organs, its pathogenesis emphasizes particularly on different fields.
Relaxing tumor pain in modern medicine, rheumatic fever, neuralgia, facial paralysis, myositis, gout etc. all can carry out determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs by arthromyodynia.About " arthromyodynia ", just have in Huangdi's Internal Classics " wet three gas of wind and cold are mixed extremely; combined into numbness; its migratory BI-syndrome caused mainly by pathogenic wind; BI-syndrome caused mainly by pathogenic cold being called painful BI; dampness victor be damp arthralgia also " record, Zhang Zhongjing is called in treatise on Febrile Diseases " severe and migratory arthralgia ", and in the pharmacy monograph Shennong's Herbal of Chinese earliest extant, record kind more than 70 treats the medicine of arthromyodynia.
Rhizoma Corydalis is the dry tuber of Papaveraceae (Papaveraeeae) Corydalis (Corydalis) plant Rhizoma Corydalis (Corydalis yanhusuo W.T.Wang), is one of famous " eight Zhe's ".Rhizoma Corydalis has another name called Rhizoma Corydalis, corydalis tuber, rhizoma corydalis, Rhizoma Corydalis, taste acrid, bitter, warm, returns liver, spleen channel, has effect of promoting blood circulation to remove blood stasis, promoting the circulation of QI to relieve pain.Rhizoma Corydalis begins to be loaded in supplement to the Herbal, in the application of China's medicine and pharmacology, the history of more than 2,000 year is had as traditional analgesic and drug for invigorating blood circulation and eliminating stasis, ancient times and modern Chinese medicine Rhizoma Corydalis are mainly used in all pain cards of stagnation of QI-blood, cure mainly obstruction of qi in the chest and cardialgia, epigastric pain, lumbago, colicky, dysmenorrhea, amenorrhea, the stagnant stomachache of the stasis of blood in puerperal, traumatic injury etc.
Summary of the invention
The invention provides the novelty teabag of Rhizoma Corydalis, namely prepare the application of Rhizoma Corydalis in preparation treatment antitumor pain medication in late period.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis, Rhizoma Corydalis total alkaloids is preparing the application in resisting rheumatoid pain medication.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, Rhizoma Corydalis total alkaloids is preparing the application in antitumor pain medication.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, Rhizoma Corydalis total alkaloids is preparing the application in antitumor pain medication in late period.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, described ancient human relations amine alkali derives from Rhizoma Corydalis total alkaloids.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, get Rhizoma Corydalis crude drug, add hydrochloric acid solution heating extraction.Merge extractive liquid, filters, concentrating under reduced pressure, and adjust ph, to alkalescence, is extracted with ethyl acetate, combined ethyl acetate layer then, and recycling design is to dry, refining, get Gu Lun amine alkali.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, is be active component by the ancient human relations amine alkali of effective dose, adds that the attend class adjuvant that accepts or complementary composition of pharmacy is prepared into conventional pharmaceutical preparation.
The invention provides a kind of pharmaceutical applications of Rhizoma Corydalis total alkaloids, it is characterized in that: described preparation is oral formulations.
Present invention also offers a kind of pharmaceutical composition for preventing and treating rheumatoid arthritis and pain thereof.It is active component by Rhizoma Corydalis total alkaloids, ancient human relations amine alkali, adds the acceptable adjuvant of pharmacy and be prepared into conventional pharmaceutical preparation.
Rhizoma Corydalis total alkaloids is from Chinese crude drug Rhizoma Corydalis, extract the alkaloid obtained.
The preparation of Rhizoma Corydalis total alkaloids
Get Rhizoma Corydalis crude drug, add acid solution heating extraction.Merge extractive liquid, filters, concentrating under reduced pressure, and adjust ph, to alkalescence, is extracted with ethyl acetate then.Combined ethyl acetate layer, recycling design, to dry, obtains Rhizoma Corydalis total alkaloids.
The preferred preparation technology of Rhizoma Corydalis total alkaloids:
Get Rhizoma Corydalis crude drug 1-3kg, add 1-5% aqueous sulfuric acid 40-80 DEG C of heating extraction 2-4 time of 5-24L.Merge extractive liquid, filters, is evaporated to 2-9L, adds 1-10%NaOH solution in right amount, and adjust ph, to 9-11, extracts 2-4 time with ethyl acetate 1-16 L then.Combined ethyl acetate layer, recycling design, to dry, obtains Rhizoma Corydalis total alkaloids.
Get Rhizoma Corydalis crude drug 1-3kg, add 1-5% aqueous sulfuric acid 40-80 DEG C of heating extraction 2-4 time of 5-24L.Merge extractive liquid, filters, is evaporated to 2-9L, adds 1-10%NaOH solution in right amount, and adjust ph, to 9-11, extracts 2-4 time with ethyl acetate 1-16 L then.Combined ethyl acetate layer, recycling design is to dry, refining, get Gu Lun amine alkali
Refining: above-mentioned Rhizoma Corydalis total alkaloids mixes sample with thick silica gel (100-200 order), through silica gel column chromatography, with acetone-methanol gradient elution (100:1 ~ 1:1).By acetone-methanol (100:1 ~ 1:1) elution fraction through the anti-phase ODS chromatographic isolation of C18 (with alcohol-water (5% ~ 100%) gradient elution), collect the alcohol elution of 25-55%, be separated (with alcohol-water (5% ~ 100%) gradient elution through polydextran gel Sephadex LH-20; Eluent flow rate 1ml/min), collect 45-85% ethanol elution fraction, after recycling design, be dissolved in methanol solution, recrystallization obtains compound ancient human relations amine alkali.
Ancient human relations amine alkali content in Rhizoma Corydalis is very low, can prepare ancient human relations amine alkali efficiently by the present invention.
Present invention also offers a kind of pharmaceutical composition for pain.It is active component by ancient human relations amine alkali, adds the acceptable adjuvant of pharmacy and be prepared into conventional pharmaceutical preparation.
Described preparation is oral formulations.
The preparation of Rhizoma Corydalis total alkaloids tablet
Prescription: Rhizoma Corydalis total alkaloids 0.5-2g, starch 50-150g, dextrin 30-100g, calcium sulfate 30-200g, magnesium stearate 1-6g.
Method for making: get Rhizoma Corydalis total alkaloids, adds starch, dextrin, calcium sulfate, magnesium stearate, mix homogeneously, makes granule, tabletting, and sugar coating or film-coat, to obtain final product.
The preparation of ancient human relations amine alkali tablet
Prescription: ancient human relations amine alkali 10-40mg, starch 50-150g, dextrin 30-100g, calcium sulfate 30-200g, magnesium stearate 1-6g.
Method for making: get ancient human relations amine alkali, add starch, dextrin, calcium sulfate, magnesium stearate, mix homogeneously, make granule, tabletting, sugar coating or film-coat, to obtain final product.
Multiple analgesic composition is had in Rhizoma Corydalis, so far from its tuber, 25 kinds are found altogether, the alkaloid of the several types such as proto-berberine, Protopine class, aporphine, benzo phenanthridines class, Phthalide iloquinoline derivative, benzylisoquinoline class, isoquinolin benzazoline class can be divided into, wherein most genus proto-berberine and aporphine by its chemical constitution.Tertiary amine base and the large class of quaternary ammonium base two then can be divided into as divided by the character of its amino nitrogen, such as corydaline, second, third, fourth, penta, oneself, heptan, pungent, ninth of the ten Heavenly Stems, the last of the ten Heavenly stems, son, ugly and third of the twelve Earthly Branches, Columbamine, (-)-Corydalmine, 13-methyl-dehydrocorydalmine, dehydrotetrahydropulmatine, palmatine, ancient human relations amine alkali, dehydrogenation Rhizoma Corydalis amine, these chemical composition energy anti-cancer pain, can angina pectoris, this contributes to the research of chemical constitution to Rhizoma Corydalis composition and analgesic activities.In Rhizoma Corydalis, the character of alkaloidal pharmacological action and its amino nitrogen is closely related, wherein tertiary amine bases many displays analgesia, calm and stable effect; And Rhizoma Corydalis resisting myocardial ischemia, reduce remarkable effect in myocardium keto consumption etc., mainly because of the existence of quaternary ammonium base constituents.
Cancer in Rhizoma Corydalis involved by multiple analgesic composition includes, without being limited to the multiple entity tumors such as pulmonary carcinoma, breast carcinoma, cancer of pancreas, gastric cancer, esophageal carcinoma, hepatocarcinoma, skin carcinoma, renal carcinoma, the brain cancer, lymphoma, tumor of nasal cavity, and the various non-solid tumors such as leukemia.
Detailed description of the invention
The preparation of embodiment 1. Rhizoma Corydalis total alkaloids
Get Rhizoma Corydalis crude drug 1kg, add 2% aqueous sulfuric acid, 50 DEG C of heating extraction 4 times of 5L.Merge extractive liquid, filters, is evaporated to 4L, and add 5%NaOH solution in right amount, adjust ph to 10, extracts 4 times with ethyl acetate 2L then.Combined ethyl acetate layer, recycling design, to dry, obtains Rhizoma Corydalis total alkaloids.
Embodiment 2
Get Rhizoma Corydalis crude drug 1kg, add 2% aqueous sulfuric acid, 50 DEG C of heating extraction 4 times of 5L.Merge extractive liquid, filters, is evaporated to 4L, and add 5%NaOH solution in right amount, adjust ph to 10, extracts 4 times with ethyl acetate 2L then.Combined ethyl acetate layer, recycling design, to dry, obtains Rhizoma Corydalis total alkaloids.
Refining: above-mentioned Rhizoma Corydalis total alkaloids mixes sample with thick silica gel (200 order), through silica gel column chromatography, with acetone-methanol gradient elution (100:1 ~ 1:1).By acetone-methanol (10:1) elution fraction through the anti-phase ODS chromatographic isolation of C18 (with alcohol-water (5% ~ 100%) gradient elution), collect the alcohol elution of 35%, be separated (with alcohol-water (5% ~ 100%) gradient elution through polydextran gel Sephadex LH-20; Eluent flow rate 1ml/min), collect 50% ethanol elution fraction, after recycling design, be dissolved in methanol solution ,-4 DEG C of recrystallization obtain compound ancient human relations amine alkali;
Embodiment 3
Get Rhizoma Corydalis crude drug 1kg, add 3% aqueous sulfuric acid, 70 DEG C of heating extraction 2 times of 6L.Merge extractive liquid, filters, is evaporated to 6L, and add 6%NaOH solution in right amount, adjust ph to 11, extracts 3 times with ethyl acetate 3 L then.Combined ethyl acetate layer, recycling design, to dry, obtains Rhizoma Corydalis total alkaloids.
Refining: above-mentioned Rhizoma Corydalis total alkaloids mixes sample with thick silica gel (200 order), through silica gel column chromatography, with acetone-methanol gradient elution (100:1 ~ 1:1).By acetone-methanol (10:1) elution fraction through the anti-phase ODS chromatographic isolation of C18 (with alcohol-water (5% ~ 100%) gradient elution), collect the alcohol elution of 35%, be separated (with alcohol-water (5% ~ 100%) gradient elution through polydextran gel Sephadex LH-20; Eluent flow rate 1ml/min), collect 50% ethanol elution fraction, after recycling design, be dissolved in methanol solution ,-4 DEG C of recrystallization obtain compound ancient human relations amine alkali;
The preparation of embodiment 4 Rhizoma Corydalis total alkaloids tablet
Prescription: Rhizoma Corydalis total alkaloids 0.5g, starch 150g, dextrin 100g, calcium sulfate 200g, magnesium stearate 2g.
Method for making: get Rhizoma Corydalis total alkaloids, adds starch, dextrin, calcium sulfate, magnesium stearate, mix homogeneously, makes granule, tabletting, and sugar coating or film-coat, to obtain final product.
The preparation of embodiment 5 ancient human relations amine alkali tablet
Prescription: ancient human relations amine alkali 20mg, starch 150g, dextrin 100g, calcium sulfate 200g, magnesium stearate 2g.
Method for making: get ancient human relations amine alkali, add starch, dextrin, calcium sulfate, magnesium stearate, mix homogeneously, make granule, tabletting, sugar coating or film-coat, to obtain final product.
Embodiment 6. Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are to the effect of the rats with arthritis that complete Freund's adjuvant is induced
Experimental technique
Rat is divided into five groups, i.e. ancient human relations amine alkali group (0.2mg/kg) that prepare of the Rhizoma Corydalis total alkaloids group (10 mg/kg) for preparing of normal group, model group, positive drug group (diclofenac sodium 10 mg/kg), embodiment 1 and embodiment 2.Inflammation is caused at rat (except normal group) right back foot intradermal injection complete Freund's adjuvant.Gastric infusion from causing scorching second day, every day is administered once, each 1mL, continues 28 days.Evaluate rat cause scorching parapodum swelling degree and arthritis index in administration the 7th day, the 14th day, the 21st day and the 28th day respectively.Administration, after 28 days, gets blood under anesthesia, surveys peripheral blood lymphocyte and neutrophil cell.Separation of serum, surveys interleukin 6 in serum (IL-6), tumor necrosis factor (TNF-α) and prostaglandin 2(PGE2 with ELISA (ELISA)) content.Rat ankle joint is fixed in 10% formalin, routine paraffin wax embedding after 10%EDTA decalcification, film-making, and HE dyes, and by pathology professional diagosis, observation synovial tissue of joint, ossa articularia, cartilage tissue damage degree are carried out scoring and compared.
Experimental result
Rhizoma Corydalis total alkaloids is on the impact of rat paw edema degree and arthritis index
So that after rat foot volume and administration, the difference (Δ mL) of the sufficient volume of rat weighs the degree of rat paw edema before scorching.As shown in table 1, contrast with normal group, model group rats causes the scorching survey remarkable swelling of foot (P < 0.05).Compared with model group, Rhizoma Corydalis total alkaloids high low dose group all significantly suppresses rat articular swelling (P < 0.05).
Table 1. Rhizoma Corydalis total alkaloids, ancient human relations amine alkali cause the impact of scorching parapodum change in volume on rat
Group causes scorching parapodum change in volume (Δ mL)
7th day, the 14th day, the 21st day, the 28th day
Normal group, 0.16 ± 0.03,0.15 ± 0.01,0.14 ± 0.04,0.15 ± 0.01
Model group, 2.52 ± 0.17,2.25 ± 0.23,2.31 ± 0.24,2.12 ± 0.35
Positive drug group, 1.23 ± 0.08,1.13 ± 0.15,0.98 ± 0.07,0.86 ± 0.15
Rhizoma Corydalis total alkaloids, 1.36 ± 0.13*, 1.23 ± 0.50*, 0.52 ± 0.08*, 0.47 ± 0.12*
Ancient human relations amine alkali, 0.92 ± 0.06*, 0.71 ± 0.03*, 0.42 ± 0.03*, 0.32 ± 0.52*
* for comparing with model group, there is significant difference (P < 0.05)
Rat arthritis index adopts 5 points of general standards, and namely 0 is divided into without changing, and 1 is divided into anklebone portion to have swelling, and 2 are divided into anklebone portion and shank portion all to have swelling, and 3 are divided into swelling to extend to metatarsal portion, and 4 are divided into whole rear foot swelling obvious.The arthritis score best result of every only tested rat is 8 points, namely two metapedes scorings add and.As shown in table 2, compare with model group, the high low dose group of Rhizoma Corydalis total alkaloids all significantly reduces rat arthritis index (P < 0.05).
Table 2. Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are on the impact of rat arthritis index
Group, arthritis index
7th day, the 14th day, the 21st day, the 28th day
Model group, 5.23 ± 0.75,6.89 ± 0.56,5.56 ± 0.21,4.32 ± 0.60
Positive drug group, 4.12 ± 0.32,2.78 ± 0.69,2.14 ± 0.23,1.52 ± 0.53
Corydalis ambigua total is biological, 4.07 ± 0.16*, 4.32 ± 0.14*, 3.12 ± 0.35*, 2.22 ± 0.34*
Ancient human relations amine alkali, 3.54 ± 0.15*, 2.72 ± 0.27*, 2.31 ± 0.28*, 1.58 ± 0.26*
* for comparing with model group, there is significant difference (P < 0.05)
Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are on the impact of Peripheral Lymphocytes of Rat and neutrophil cell
As shown in table 3, compare with normal group, model group rats peripheral blood lymphocyte significantly reduces (P < 0.05), and neutrophil cell significantly raises (P < 0.05).Rhizoma Corydalis total alkaloids high low dose group compares with model group, and peripheral blood lymphocyte all significantly raises, and neutrophil cell all significantly reduces.
Table 3. Rhizoma Corydalis total alkaloids is on the impact of Peripheral Lymphocytes of Rat and neutrophil cell
Group lymphocyte count (10
6) neutrophil cell counting (10
6)
Normal group, 156.21 ± 5.52,45.75 ± 2.52
Model group, 79.22 ± 2.45,102.87 ± 6.02
Positive drug group, 115.52 ± 6.38,68.13 ± 1.96
Rhizoma Corydalis total alkaloids, 123.63 ± 7.26*, 36.17 ± 1.25*
Ancient human relations amine alkali, 136.6 ± 2.14*, 42.21 ± 1.56*
* for comparing with model group, there is significant difference (P < 0.05)
(1) Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are on the impact of rat blood serum IL-6, TNF-α and PGE2 content
In model group rats serum, the content of IL-6, TNF-α and PGE2 compares significance and improves (P < 0.05) with normal group.In Rhizoma Corydalis total alkaloids extract, ancient human relations amine alkali rat blood serum, the level of IL-6, TNF-α and PGE2 and model group contrast, and equal significance reduces (P < 0.05).。
Table 4. Rhizoma Corydalis total alkaloids is on the impact of rat blood serum IL-6, TNF-α and PGE2 content
Group, IL-6 (pg/mL), TNF-α (pg/mL), PGE2 (pg/mL)
Normal group, 35.78 ± 1.23,51.24 ± 1.89,31.48 ± 2.56
Model group, 78.14 ± 3.26,121.3 ± 5.31,98.45 ± 4.23
Positive drug group, 38.79 ± 1.75,87.56 ± 4.89,56.21 ± 3.75
Rhizoma Corydalis total alkaloids, 36.12 ± 2.46*, 78.12 ± 3.92*, 52.12 ± 1.52*
Ancient human relations amine alkali, 32.12 ± 1.23*, 58.46 ± 1.15*, 42.51 ± 1.64*
* for comparing with model group, there is significant difference (P < 0.05)
(2) Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are on the impact of rat articular pathological change
Rat ankle joint is fixed in 10% formalin, routine paraffin wax embedding after 10%EDTA decalcification, film-making, and HE dyes, and by pathology professional diagosis, observation synovial tissue of joint, ossa articularia, cartilage tissue damage degree are carried out scoring and compared.According to each site morbidity light and heavy degree, be quantitatively 0 to 4 point successively.1 point (slightly), 2 points (moderate), 3 points (severe), 4 points (pole severe), 0 point (normal).Cumulative all marks, draw and often organize average mark.
Result shows, and the synovial membrane surface of normal rats is covered with 1-4 layer synovial cell, without obvious degeneration, necrosis, without hypertrophy.Joint facial bone and cartilaginous tissue are without degeneration, necrosis.Surrounding skin has no inflammatory reaction.
Synovial cell's moderate degeneration of model group rats, synovial tissue's moderate is congested, and inside have cell infiltration, inflammatory cell type is mainly mononuclear phagocyte and neutrophilic granulocyte.Have a large amount of cell infiltration in corium and subcutaneous tissue, inflammatory cell type is mainly mononuclear phagocyte, lymphocyte and a small amount of neutrophilic granulocyte.
Compare with model group, Rhizoma Corydalis total alkaloids, ancient human relations amine alkali is ameliorate osteoarthritis pathological changes all significantly.
Table 5. Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are on the impact of rat articular pathological change
Group, animal number of elements, pathological change is marked
Normal group, 10,0.00 ± 0.00
Model group, 10,6.00 ± 0.36
Positive drug group, 10,1.89 ± 0.42
Rhizoma Corydalis total alkaloids, 10,1.42 ± 0.18*
Ancient human relations amine alkali, 10,0.78 ± 0.11*
For comparing with model group, there is significant difference (P < 0.05)
Embodiment 7 Rhizoma Corydalis total alkaloids, ancient human relations amine alkali are to the effect of S180 sarcoma compressing mice sciatic nerve cancer pain model
Laboratory animal, tumor strain and medicine BALB/c mouse, male and female half and half, body weight 18 ~ 22 g.The raw work in S180 tumor strain Shanghai is bought.
Animal is screened
The Mus choosing pain threshold 2-7 s before experiment is qualified Mus.Water-bath is heated to 55 DEG C, mice is fixed, afterbody vertically downward, after the peace and quiet of band Mus, Mus afterbody is put into water-bath 55 DEG C of water (it is basically identical that each Mus afterbody enters water distance), treating that Mus tail throws away the water surface is completely pain reaction, calculates and puts into water to the time throwing away the water surface from Mus tail, is this Mus pain threshold with this time.
Animal divides into groups
At random mice is divided at random blank group, ancient human relations amine alkali group (0.2mg/kg) that prepare of the Rhizoma Corydalis total alkaloids group (10 mg/kg) for preparing of model group, positive drug group (diclofenac sodium 10 mg/kg), embodiment 1 and embodiment 2 by Basic Pain Threshold value and body weight.Often organize 10 (male and female sub-cage rearing).After the inoculation of S180 sarcoma cell, the same day plays gastric infusion, and every day is administered once, each 1mL,
S180 sarcoma cell is inoculated
S180 sarcoma cell is inoculated in mouse peritoneal, after cultivating 7 d, select the mice that the mental status is good, ascites is full, extracting ascites is tumor source, by ascites with after normal saline dilution 5 times, extract dilution after carry about 2 × 106 tumor cells of mice with tumor ascites 0.2 mL(), be inoculated in the muscle around the right lower limb sciatic nerve of mice.Keep room temperature at 20 ~ 25 DEG C, relative humidity 40% ~ 60%; Ad lib and drinking-water; For keeping animal tight knot rule round the clock, laboratory 8:00 to 20:00 every day turns on light, and 20:00 turns off the light to 8:00 next day, observes the growing state of the general status of mice, changes of body mass and tumor every day.
, model group mice goes out the hard lump of reality at tumor injection position in first week in modeling, and increases gradually.Behavioristics's performance starts from modeling the 9th day, occurs that sciaticnerve lesions is levied, lifts, shakes and lick right hind, in dragging foot, jump gait, and exhibition pawl areflexia.When cage covers walking, right foot grips obstacle, from mesh, easily steps on sky leak down.And strengthen continuously; engender the performance of sensory disturbance; there is idiopathic pain symptoms such as lifting right hind, shake, do not bear a heavy burden gradually frequently; and phase after the test, model group individual mice occurs that Ipsilateral protectiveness is lifted, phenomenon of can not contacting to earth; when Pain behaviour is tested; even if pressure large again, does not also react, it is caused by neural paralysis that reason is thought of as one.Further illustrate the success of this test model.
Method of testing
Experiment adopts Mus tail tenderness method to measure pain threshold, and each group is carried out respectively after the inoculation of S180 sarcoma cell on the the 1st, 3,5,7,9,11,13,15,17 day.Be placed in by mice in holder, afterbody is exposed to outside holder, tests after animal peace and quiet.Labelling is carried out apart from tail point 1/3 place as compression point at mouse tail before surveying pain.Occur struggling or shouting as pain reaction index using mice when exerting pressure, this force value is this Mus pain threshold.During replication, the strong point can slightly move, in order to avoid weigh tissue wounded.
Statistical method
All experimental datas represent with x ± s, and measurement data is undertaken checking between variance analysis and group by SPSS13.0 statistical software.With P <0.05 for there being obvious significant difference.
Result
Constantly rised in value and sciatic nerve crush by tumor cell in experiment, produce pain.Show from Pain behaviour result of study, from S180 sarcoma cell is inoculated the 9th day, there is notable difference in the Rhizoma Corydalis total alkaloids group (10 mg/kg) that blank group, model group, positive drug group (diclofenac sodium 10 mg/kg), embodiment 1 prepare and ancient human relations amine alkali group (0.2mg/kg) pain threshold that embodiment 2 prepares, the 11st, 13,15,17 day model group and blank group, matched group pain threshold also occur notable difference.
Group (Basic Pain Threshold value), the 9th day, the 11st day, the 13rd day, the 15th day, the 17th day
Blank group, 241.2 ± 15.1,239.5 ± 14.7,252.0 ± 12.3,248.3 ± 10.6,245.7 ± 10.6
Model group, 150.6 ± 17.3,115.2 ± 13.1,101.2 ± 12.3,98.1 ± 13.2,81.7 ± 10.6
Positive drug group, 170.5 ± 16.7,135.3 ± 12.1,128.3 ± 10.2,118.7 ± 14.5,109.3 ± 14.2
Rhizoma Corydalis total alkaloids, 189.2 ± 17.8,167.6 ± 14.1,165.2 ± 10.1,136.2 ± 13.1,121.1 ± 16.1
Ancient human relations amine alkali, 178.6 ± 12.4,175.2 ± 13.4,181.3 ± 12.1,187.1 ± 14.1,176.1 ± 13.8
Embodiment 8 thin layer chromatography:
Adsorbent: silica gel G thin layer precoated plate (Qingdao);
Developing solvent: ethyl acetate-isopropanol-methanol-ammonia (10: 4: 1.5: 0.5: 1),
Embodiment 2 sample 1 μ L point plate,
Launch temperature room temperature, presaturation 15min before launching, exhibition distance 10cm,
Take out, dry, inspect under putting ultra-violet lamp (365nm).
Only there is unique speckle in 8.1cm.
Embodiment 9 high performance liquid chromatography:
Chromatographic column take octadecylsilane chemically bonded silica as filler; Shimadzu liquid phase instrument
Mobile phase is acetonitrile-1% acetic acid aqueous solution (20: 80 volume ratio), isocratic elution;
Flow velocity 1.0mL/min; Column temperature 30 DEG C; Determined wavelength 280nm.
Under these conditions, draw respectively and remove embodiment 2 sample (mobile phase solution) 10 μ L, inject high performance liquid chromatograph and analyze,
1 chromatographic peak in this collection of illustrative plates, appearance time 21.52 minutes, peak area 8963547.52AU.
Claims (7)
1. a pharmaceutical applications for Rhizoma Corydalis, is characterised in that the application of Rhizoma Corydalis in preparation treatment antitumor pain medication in late period.
2. a pharmaceutical applications for Rhizoma Corydalis total alkaloids, is characterised in that the application of Rhizoma Corydalis total alkaloids in the anti-pain medication of preparation.
3. a pharmaceutical applications for Rhizoma Corydalis total alkaloids, is characterised in that Rhizoma Corydalis total alkaloids is preparing the application in antitumor pain medication in late period.
4. purposes according to claim 1, is characterized in that: described ancient human relations amine alkali derives from Rhizoma Corydalis total alkaloids.
5. purposes according to claim 1, is characterized in that: get Rhizoma Corydalis crude drug, adds hydrochloric acid solution heating extraction, merge extractive liquid, filter, concentrating under reduced pressure, adjust ph, to alkalescence, is extracted with ethyl acetate then, combined ethyl acetate layer, recycling design is to dry, refining, get Gu Lun amine alkali.
6. treat a pharmaceutical composition for pain, it is characterized in that: be active component by the ancient human relations amine alkali of effective dose, add that the attend class adjuvant that accepts or complementary composition of pharmacy is prepared into conventional pharmaceutical preparation.
7. pharmaceutical composition according to claim 5, is characterized in that: described preparation is oral formulations.
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| WO2020062545A1 (en) * | 2018-09-29 | 2020-04-02 | 泰州医药城国科化物生物医药科技有限公司 | Method for preparing tertiary amine basic components in rhizoma corydalis |
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