CN100382817C - Collateral channels clearing arthralgia dredging prescription for treating rheumatoid arthritis and its preparing process - Google Patents
Collateral channels clearing arthralgia dredging prescription for treating rheumatoid arthritis and its preparing process Download PDFInfo
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Abstract
The present invention discloses a medicine for promoting channel penetration and treating rheumatism, which is used for treating rheumatoid arthritis. The medicine is mainly composed of raw material medicines, such as rehmannia root, orientvine stem, Chinese taxillus herb, common St. Paulswort, notoginseng powder, stir-baked bombyx batryticatus, tripterygium wilfordii, Chinese starjasmine stem, etc. The preparation method of the present invention comprises decoction by water, micro-filtration of the decocted solution, decompression concentration, spray drying, auxiliary material addition and granulation by a dry method. The pharmaco-pharmacodynamic experiment and the clinical application prove that the medicine has the advantages of obvious treatment effect, rich medicine resources, low cost, convenient utilization, no obvious poison side effect, broad market effect at home and abroad, good development prospects, and obvious social and economic benefit after popularized and applied, and furthermore, the clinical treatment effect rate is 38.10%, and the total effective rate is 90.48%.
Description
One, technical field
The present invention relates to technical field of Chinese medicines, specifically relating to a kind of is the medicine and preparation method thereof of the treatment rheumatoid arthritis made of raw material with the vegetable Chinese herbal medicine.
Two, background technology
Rheumatoid arthritis (abbreviation quasi-wind gateway) still belongs to agnogenic obstinate disease at present at home and abroad, and is very big to labour force's influence.In recent years, western medicine is to the pathogenetic research of quasi-wind gateway, deeply to the molecular immune level, but treatment to quasi-wind gateway, it is recent, late result all is difficult to satisfactory, finally fail to stop destructive pathological changes { Zhang Naizheng, rheumatismal Clinics and Practices, the practical internal medicine journal 1992 of sclerotin; 12 (12): 631}, still do not have specific short.Clinical practice is nonsteroidal antiinflammatory drug the most widely, can not stop its PD, and prolonged application can cause serious gastrointestinal side effect; Though 17-hydroxy-11-dehydrocorticosterone can be controlled clinical symptoms preferably, finally can not stop the destructive pathological changes of quasi-wind gateway, and continue to take side effect above its therapeutical effect; International change state of an illness medicine such as immunosuppressant etc., though certain inhibition state of an illness effect is arranged, but what reach the clinical cure standard after the medication is no more than 10%, and certain toxicity is arranged all, can cause patient to occur than serious adverse effects { Jiang Ming, strengthen the clinical research of rheumatoid arthritis, Chinese Medical Journal 1998; 78 (3): 165}.Chinese medicine has bigger progress to the research of quasi-wind gateway, take a broad view of the various places report, clinical effective rate is about about 80～90%, but still difficulty makes a breakthrough, the clinical cure obvious effective rate is still low, and the Chinese patent medicine of clinical practice at present is mostly according to the differential diagnosis of diseases prescription, and the property of medicine is partial to warm-dryness syndrome, as YISHEN JUANBI WAN, Wang numbness electuary etc., be not suitable for the patient of dialectical genus pyretic arthralgia; Preparations such as Colquhounia coccinea Wall. var. mollis (Schlecht.) Prain heel piece, Radix Tripterygii Wilfordii tablet are toxic side effect and non-indication { Huang Liping, the Chinese and western medicine medicine therapeutic advance of rheumatoid arthritis, Colleges Of Traditional Chinese Medicine Of Guangxi's journal 1999 also; 16 (2): 89; Chen Jifan, the problem that exists in the advantage of Chinese medicine rheumatoid arthritis and the research, the new traditional Chinese medical science 1998; 30 (4): 63}.The quality of compound Chinese medicinal preparation and scientific and technological content are also in urgent need to be improved.Therefore, Chinese medicine treatment level and the quickening modernization of Chinese medicine and the industrialization process of this research to improving quasi-wind gateway has extremely important meaning.
Three, summary of the invention
1, goal of the invention
The purpose of this invention is to provide medicine of a kind of treatment rheumatoid arthritis evident in efficacy and preparation method thereof.
2, technical scheme
A, a kind of clear ruton numbness preparation for the treatment of rheumatoid arthritis is characterized in that the prescription that mainly contains following weight proportion forms:
The Radix Rehmanniae 10～25g Caulis Sinomenii 10～25g Herba Taxilli 10～25g Herba Siegesbeckiae 10～25g
Radix Notoginseng powder 2～6g Bombyx Batryticatus(processed) 10～15g Radix Tripterygii Wilfordii 5～15g Caulis Trachelospermi 10～25g
Lay particular stress on when damp and hot, the yellow and greasy fur person can add Rhizoma Smilacis Glabrae 10～25g, Cortex Phellodendri 5～15g in addition;
When stagnant heat lays particular stress on, skin erythema, the dark violet person of body of the tongue can add Radix Salviae Miltiorrhizae 10～25g in addition, Ramulus Euonymi 10～25g, Flos Campsis 10～25g;
Work as arthroncus, then can add Fructus Liquidambaris 10～25g, Herba Aristolochiae 10～25g in addition.
The preparation method of B, clear ruton numbness preparation, its concrete steps are as follows:
(1) eight of clear ruton numbness preparation flavors are got Radix Notoginseng powder and are broken into superfine powder; 7 flavors such as all the other Radix Rehmanniae decoct with water 2 times, and 11 times of water gagings decocted 1.5 hours for the first time, and 7 times of water gagings decocted 1.0 hours for the second time;
(2) merge decoction liquor, microfiltration (filter material is an inorganic ceramic film, and the aperture is 0.2 μ m); Filtrate decompression thin film concentration (0.085Mpa, 65-70 ℃) is to relative density 1.08～1.10 (60 ℃);
(3) spray drying (170 ℃ of inlet temperature, 70 ℃ of leaving air temps);
(4) mixing behind the dry powder adding Radix Notoginseng superfine powder;
(5) add appropriate amount of auxiliary materials, mixing, dry granulation (rolling process, 20～60 orders), packing, promptly.
Above-mentioned adjuvant is dextrin and stevioside.
3, beneficial effect
Clear ruton numbness preparation is followed theory of Chinese medical science on research ideas and methods, reaching dialectical combines with differential diagnosis of diseases, clinical efficacy is obviously improved, the clinical cure obvious effective rate is 38.10%, total effective rate is 90.48%, obviously be better than 20%, 83.64% of Glucosidorum Tripterygll Totorum matched group, obvious adverse reaction does not appear in clear ruton numbness preparation patient in therapeutic process, and the adverse reaction rate of Glucosidorum Tripterygll Totorum is up to 49.09%.Studies show that: said preparation can improve patient's quality of life; reduce disability rate; protection social labor power; and the medicine source is abundant, cheap, taking convenience, no obvious toxic-side effects; vast market and excellent development prospect are at home and abroad arranged, will obtain remarkable social benefit and economic benefit after applying.
Four, preferred forms
(1) embodiment one: the basic prescription of clear ruton numbness preparation
Radix Rehmanniae 15g Caulis Sinomenii 15g Herba Taxilli 15g Herba Siegesbeckiae 15g
Radix Notoginseng powder 3g Bombyx Batryticatus(processed) 10g Radix Tripterygii Wilfordii 5g Caulis Trachelospermi 15g
Lay particular stress on when damp and hot, the yellow and greasy fur person can add Rhizoma Smilacis Glabrae 15g, Cortex Phellodendri 10g in addition;
When stagnant heat lays particular stress on, skin erythema, the dark violet person of body of the tongue can add Radix Salviae Miltiorrhizae 15g in addition, Ramulus Euonymi 15g, Flos Campsis 15g;
Work as arthroncus, then can add Fructus Liquidambaris 15g, Herba Aristolochiae 15g in addition.
(2) embodiment two: the preparation method of clear ruton numbness preparation
Eight herbal medicines of clear ruton numbness preparation are got Radix Notoginseng powder and are broken into superfine powder; 7 flavors such as all the other Radix Rehmanniae decoct with water 2 times, and 11 times of water gagings decocted 1.5 hours for the first time, and 7 times of water gagings decocted 1.0 hours for the second time; Merge decoction liquor, microfiltration (filter material is an inorganic ceramic film, and the aperture is 0.2 μ m); Filtrate decompression thin film concentration (0.085Mpa, 65-70 ℃) is to relative density 1.08～1.10 (60 ℃), spray drying (170 ℃ of inlet temperature, 70 ℃ of leaving air temps); Dry powder adds the Radix Notoginseng superfine powder, adds an amount of dextrin and stevioside, mixing, and dry granulation (rolling process, 20～60 orders), packing, promptly.
(3) embodiment three: the pharmacological effect test
1 experiment material
1.1 medicine and reagent
The clear every bag of ruton arthralgia eliminating granule 5g contains crude drug 2.5g/g, is provided by Nanjing University of Traditional Chinese Medicine plant amedica deep processing center.Used animal dosage calculates with amount of formulation in the experiment, is made into desired concn with preceding with normal saline.
Carrageenin, azovan blue (Evan ' s blue), Glucosidorum Tripterygll Totorum, etidocine tablet, glacial acetic acid, bacillus calmette-guerin vaccine, viviparous Ox blood serum, MTT, ConA, LPS,
3H-TdR, PGE
2The RIA test kit.
1.2 animal
SD rat, ICR mice provide by Nanjing University of Traditional Chinese Medicine's Experimental Animal Center.
2 methods and result
2.1 the anti-inflammatory and analgesic effect of clear ruton arthralgia eliminating granule research
2.1.1 clear ruton arthralgia eliminating granule brings out the influence of foot swelling to rat carrageenan
Get 50 of male rats, 180-220g is divided into five groups at random, i.e. (1) model group: normal saline 10ml/kg; (2) Tripterygium glycosides group: 7.5mg/Kg; (3) clear ruton numbness small dose group 3.6g crude drug/kg; (4) dosage group 7.2g crude drug/kg in the clear ruton numbness; (5) the heavy dose of group of clear ruton numbness 14.4g crude drug/kg.Each group is pressed the 10ml/kg gastric infusion, gives 3 altogether.Behind the last administration 30min, at rat right hind leg foot plantar subcutaneous injection 1% carrageenin 0.05ml/ only, with volumetric method measure cause scorching before with cause scorching back 30,60,120,240min rat paw volume.So that the difference of sufficient sole of the foot volume is the swelling degree before and after scorching, the results are shown in Table 1.
The clear ruton arthralgia eliminating granule on Carrageenan of table 1 bring out rat paw edema influence (X ± S, n=10)
* P＜0.05 * * P＜0.0l and model group are relatively
Dosage in the clear ruton arthralgia eliminating granule of table 1 presentation of results, heavy dose of two dosage group on Carrageenan are brought out rat paw edema that the obvious suppression effect is arranged, and are particularly evident with 60min, 120min inhibitory action.
2.1.2. clear ruton arthralgia eliminating granule is to the swollen influence that forms of rat granuloma
Get 50 of male rats, body weight 180-220g implants oxter, the rat left and right sides, skin suture, sterilization respectively with two 10mg sterilization cotton balls.Be divided into five group with rat next day, i.e. (1) model group: normal saline 10ml/kg; (2) Tripterygium glycosides group: 7.5mg/Kg; (3) clear ruton numbness small dose group 3.6g crude drug/kg; (4) dosage group 7.2g crude drug/kg in the clear ruton numbness; (5) the heavy dose of group of clear ruton numbness 14.4g crude drug/kg.Each group is pressed the 10ml/kg gastric infusion, gives 8 altogether.Take off vertebra execution rat next day after the drug withdrawal, takes out cotton balls, rejects fatty tissue.Take by weighing the dry weight (60 ℃ of oven dry) of cotton balls, calculate granulation tissue dry weight and suppression ratio thereof, the results are shown in Table 2.
The clear ruton arthralgia eliminating granule of table 2 to the swollen influence that forms of rat granuloma (x ± S, n=10)
Compare * * P＜0.01 with model group
Table 2 is the result show: dosage, heavy dose of two dosage groups all can obviously reduce granulation tissue weight in the clear ruton numbness, with model group significant difference (P＜0.01) are arranged relatively.
2.1.3 clear ruton arthralgia eliminating granule is to the influence (hot plate method) of the pain caused reaction of mice thermostimulation
Get the 18-22gICR female mice, constant temperature (55 ± 0.5 ℃) thermostimulation causes pain, measures pain threshold (licking metapedes with mice is pain reaction information, and be the threshold of pain index incubation period of reacting with pain, is qualified mice if the threshold of pain is no more than 30s) in advance.Select 50 of qualified mices, be divided into five groups at random, be i.e. (1) model group: normal saline 10ml/kg; (2) indometacin group: 12.5mg/Kg; (3) clear ruton numbness small dose group 7.2g crude drug/kg; (4) dosage group 14.4g crude drug/kg in the clear ruton numbness; (5) the heavy dose of group of clear ruton numbness 28.8g crude drug/kg.Each organizes equal gastric infusion three days, and after the last administration 30,60,90,120min respectively surveys its pain threshold.The results are shown in Table 3.
The clear ruton arthralgia eliminating granule of table 3 to the analgesic activity (hot plate method) of mice (x ± SD, n=10)
Compare #P＜0.05 ##P＜0.01 with comparison * P＜0.05 * * P＜0.01 before the administration with the normal saline group
Table 3 is the result show: three dosage groups of clear ruton arthralgia eliminating granule all can improve the pain threshold of mice in various degree, with before the administration and the model group comparing difference remarkable.
In addition, also observed clear ruton arthralgia eliminating granule to the influence (writhing method) of the influence of mouse peritoneal capillary permeability and clear ruton arthralgia eliminating granule to the pain caused reaction of mice chemical stimulation.The result shows: dosage group, heavy dose of two increases that the dosage group all can obviously be resisted the permeability of acetic acid induced mice abdominal cavity blood capillary in the clear ruton numbness; Dosage, heavy dose of two dosage groups can significantly reduce the mouse writhing reaction times in the clear ruton numbness.
2.1.4 discuss
Rheumatoid arthritis is the arthropathy based on synovitis, and pathological process has inflammation (ooze out, soak into), hypertrophy, granulation tissue to form all stages, clinical pain, swelling, the moving obstacle that mainly shows as the joint.Therefore, antiinflammatory, analgesia are the basic pharmacological effects of ruton arthralgia eliminating granule treatment rheumatoid arthritis clearly.This experimental result shows: clear ruton arthralgia eliminating granule can suppress the formation of rat carrageenan foot swelling and granuloma induced by implantation of cotton pellets, reduces the permeability of mouse peritoneal blood capillary, prompting to inflammation ooze out, the hypertrophy of edema and collagen fiber has the obvious suppression effect; Clear ruton arthralgia eliminating granule can alleviate the painful reaction of the mice due to thermostimulation, the chemical stimulation, shows that the clear ruton arthralgia eliminating granule of doses has antiinflammatory and analgesic activity preferably.
2.2 the influence that clear ruton arthralgia eliminating granule changes the adjuvant arthritis rats inflammation
2.2.1 clear ruton arthralgia eliminating granule is to the influence of the primary affection of adjuvant-induced arthritis
Get 60 of male rats, 160-200g is divided into six groups at random, i.e. 1. normal control group: normal saline 10ml/kg; 2. model group: normal saline 10ml/kg; 3. Glucosidorum Tripterygll Totorum group: Glucosidorum Tripterygll Totorum 7.5mg/kg; 4. clear ruton numbness small dose group 3.6g crude drug/kg; 5. dosage group 7.2g crude drug/kg in the clear ruton numbness; 6. the heavy dose of group of clear ruton numbness 14.4g crude drug/kg.Each group is pressed the 10ml/kg gastric infusion, gives 5 altogether.Behind administration 30min on the 3rd, except that the normal saline group, organize the right back sufficient sole of the foot intradermal injection Freund's complete adjuvant 0.05ml/ of rat (wherein containing bacillus calmette-guerin vaccine 7.5mg/ml) at each, normal saline group rat continued administration 2 days then at its right back sufficient sole of the foot intradermal injection equivalent normal saline.With volumetric method measure cause scorching before with cause scorching back 12,18,24,48h rat paw volume so that the difference of sufficient sole of the foot volume is the swelling degree before and after scorching.The results are shown in Table 4.
The clear ruton arthralgia eliminating granule of table 4 to Freund's complete adjuvant cause the foot swelling of rat primary affection influence (x ± s, n=10)
* compare with matched group P＜0.05 P＜0.01
ΔP＜0.05
The Δ ΔCompare with model group P＜0.01
Table 4 is the result show: clear three dosage groups of ruton numbness all can reduce the paw swelling of rat primary affection due to the Freund's complete adjuvant in various degree, with model group comparing difference significantly (P＜0.05, P＜0.01=.
2.2.2 clear ruton arthralgia eliminating granule is to the influence of polyarthritis (Secondary cases pathological changes)
Get 60 of male rats, 160-200g, randomly draw 10 and only be injected in right back sufficient sole of the foot Intradermal with normal saline 0.05ml/, in addition 50 with Fu Shi (Freund ' s) Freund's complete adjuvant 0.05ml/ only (wherein containing bacillus calmette-guerin vaccine 7.5mg/ml) be injected in right back sufficient sole of the foot Intradermal, after causing a scorching week rat is divided into five groups at random, adds that the normal control group is 6 groups altogether.I.e. 1. normal control group: normal saline 10ml/kg; 2. model group: normal saline 10ml/kg; 3. Glucosidorum Tripterygll Totorum group: Glucosidorum Tripterygll Totorum 7.5mg/kg; 4. clear ruton numbness small dose group 3.6g crude drug/kg; 5. dosage group 7.2g crude drug/kg in the clear ruton numbness; 6. the heavy dose of group of clear ruton numbness 14.4g crude drug/kg.Each organizes gastric infusion 1 time every day, successive administration 21 days.And measure sufficient sole of the foot volume about rat (measuring) with volumetric method before injection adjuvant and behind the injection adjuvant respectively at the 8th, 10,14,18,22,28 day.Is swelling degree (ml) with the parapodum sole of the foot in the difference of giving adjuvant front and back volume, the pathological changes of observing positions such as rat forelimb performance, ear, afterbody simultaneously.Put to death then and respectively organize rat, get adrenal gland, thymus, spleen immediately and weigh, and rat ankle joint is carried out the arthropathology inspection.The results are shown in Table 5,6,7,8,9.
The clear ruton arthralgia eliminating granule of table 5 causes the influence (right foot) of rat secondary affection foot swelling to Freund's complete adjuvant, and (x ± * P＜0.05 * * P＜0.01 and normal control group are relatively
ΔP＜0.05
The Δ ΔCompare with model group P＜0.01
* compare with the normal control group P＜0.05 * * P＜0.01
ΔP＜0.05
The Δ ΔCompare with model group P＜0.01
The clear ruton arthralgia eliminating granule of table 6 to Freund's complete adjuvant cause the foot swelling of rat secondary affection influence (left side foot) (x ± s, n=10)
* compare with the normal control group P＜0.05 * * P＜0.01
ΔP＜0.05
The Δ ΔCompare with model group P＜0.01
Table 5,6 results show, clear three dosage groups of ruton arthralgia eliminating granule can obviously suppress rat that Freund's complete adjuvant causes and cause the foot swelling that scorching side and offside hind leg cause because of delayed hypersensitivity, relatively have significant difference (P＜0.05, P＜0.01) with model group.
The clear ruton arthralgia eliminating granule of table 7 is to the nodular influence of Freund's complete adjuvant rats with arthritis
Compare with the normal control group * P＜0.01
ΔP＜0.05
The Δ ΔCompare with model group P＜0.01
Table 7 is the result show, the model group rat is caudal articular process nodosity shape projection after 12 days, is beading.Forelimb and ear do not have tuberosity, but ear has punctation to occur.Clear ruton arthralgia eliminating granule can reduce above-mentioned nodular incidence rate, and wherein heavy dose is organized and compared with model group that there was a significant difference (P＜0.05).
The clear ruton arthralgia eliminating granule of table 8 is to the influence of adjuvant arthritis rats thymus, spleen, adrenal gland's weight (x ± s)
* compare with model group P＜0.05.
Table 8 is the result show, clear ruton arthralgia eliminating granule does not have obvious influence to adjuvant arthritis rats thymus, spleen, adrenal gland's weight, compares difference with model group and does not have significance (P＞0.05).
2.2.3 clear ruton arthralgia eliminating granule is to the histological influence of adjuvant arthritis rats joint pathology
The clear ruton arthralgia eliminating granule of table 9 is to the histological influence of adjuvant arthritis rats joint pathology (right foot)
By experimental result as can be seen, tangible articular cartilage appears in adjuvant arthritis rats to be destroyed, fibrosis, synovial membrane has congested in various degree, edema and a large amount of cell infiltration, granulation tissue hyperplasia, confirm that this treated animal model has the pathological characters of rheumatoid arthritis, rheumatoid synovial, the class pannus changes and proliferative, there are [67] simultaneously in destructive pathological changes, and change basically identical [68] with the experimental rheumatoid arthritis rat model of domestic report pathomorphology, illustrate that modelling is successfully reliable, clear three dosage groups of ruton numbness can be improved above-mentioned pathological changes in various degree, can reduce the rat articular cartilage destroys, synovial membrane inflammation, granulation tissue forms, the pass joint number of soft tissue inflammation outside the joint, and can alleviate its pathological change degree.
2.2.4 clear ruton arthralgia eliminating granule is to the Ultrastructural influence in adjuvant arthritis rats joint
Choose the Ultrastructural observation that 1 rat does the joint for every group.Specimen is with the fixing 2h of 5% glutaraldehyde, and reuse 1% osmic acid is 1h fixedly, and conventional dehydration with epoxy resin 618 embeddings, is used acetic acid uranium behind the ultrathin section---the lead citrate double staining, under transmission electron microscope, observe ultrastructure.
Model group: Fibroblast Function is active, collagen fiber are many and intensive, mastocyte is more under the synovial membrane sees, capillary wall obviously thickens, tube chamber is narrow, organelle is abundant in the endotheliocyte kytoplasm, more commonly around common mitochondrial swelling and the more vesicle, blood vessel contains more lysosomal cell.
The heavy dose of group of clear ruton arthralgia eliminating granule: synovial cell and fibroblast do not have obvious hypertrophy, and the collagen fiber bunchy is arranged, and seeing has a small amount of lymphocyte and macrophage to be distributed in the connective tissue, and blood capillary is normal substantially.
2.2.5 discuss
This experimental result shows, three dosage groups all can reduce the paw swelling of rat assist agent arthritis primary affection due to the Freund's complete adjuvant in various degree; The secondary affection that can obviously suppress the rat assist agent arthritis that Freund's complete adjuvant causes: comprise and suppress to cause the foot swelling that scorching side and offside hind leg cause because of delayed hypersensitivity, reducing caudal articular process has the incidence rate of beading nodules shape projection, still serves as obvious with heavy dose group effect; Clear three dosage groups of ruton numbness can be improved the adjuvant arthritis rats articular cartilage in various degree and destroy synovial membrane inflammation and granulation tissue formation, soft tissue inflammation and Ultrastructural change outside the joint.The above results prompting, the clear ruton arthralgia eliminating granule of doses can prevent inflammation and the disorganization organized adjuvant arthritis rats joint and joint outside, and the primary affection and the secondary affection of adjuvant arthritis rats all had obvious inhibitory action.
2.3 clear ruton arthralgia eliminating granule is to the influence of adjuvant arthritis rats T lymphproliferation response and bone-marrow-derived lymphocyte breeder reaction
2.3.1 the making of model, grouping and processing:
Get 60 of male rats, 160-200g, randomly draw 10 and only be injected in right back sufficient sole of the foot Intradermal with normal saline 0.05ml/, in addition 50 with Fu Shi (Freund ' s) Freund's complete adjuvant 0.05ml/ only (wherein containing bacillus calmette-guerin vaccine 7.5mg/ml) be injected in right back sufficient sole of the foot Intradermal, after causing a scorching week rat is divided into five groups at random, adds that the normal control group is 6 groups altogether.I.e. 1. normal control group: normal saline 10ml/kg; 2. model group: normal saline 10ml/kg; 3. Glucosidorum Tripterygll Totorum group: Glucosidorum Tripterygll Totorum 7.5mg/kg; 4. clear ruton numbness small dose group 3.6g crude drug/kg; 5. dosage group 7.2g crude drug/kg in the clear ruton numbness; 6. the heavy dose of group of clear ruton numbness 14.4g crude drug/kg.Each organizes gastric infusion 1 time every day, successive administration 21 days.
2.3.2 collection of specimens and processing
Randomly draw 4 rat carotid artery sacrificed by exsanguination with every group, put into 1: 1000 bromo geramine and soak, open abdomen and get spleen, spleen nylon wire parcel is put into culture dish, grind, then splenocyte suspension is put into centrifuge tube with nook closing member, remove supernatant after centrifugal, add 0.83%NH
4Cl solution (removal erythrocyte) back is centrifugal, abandons supernatant, adds D-Hank ' s liquid flushing 2 times, carries out cell counting [total cellular score=(four big grid cell number ÷ 4) * 10 after centrifugal
4* extension rate], be mixed with 1 * 10 with the RPMI-1640 culture fluid
10The splenocyte suspension of/L adds 96 well culture plates, every hole 100 μ l, (final concentration of ConA is 3mg/L to add the RPMI-1640 liquid 100 μ l that contain ConA or LPS again, the final concentration of LPS is 12mg/L) put 37 ℃ of 5%CO2 incubators and cultivate 48h, inhale gently and abandon supernatant 100 μ l, add MTT (5mg/ml) 10 μ l, in agitator vibration 1min, place 37 ℃ of reactions of 5%CO2 incubator 4h, take out reactant, centrifugal (1800rpm, 10min) supernatant is abandoned in suction, every hole adds acidify isopropyl alcohol 120 μ l, the 30s that on agitator, vibrates, and microplate reader 570nm reads at the place A value.
2.3.3 statistical method
Data are represented with X ± S, relatively adopt the t check relatively of two sample means between each group.
2.3.4 experimental result
The clear ruton arthralgia eliminating granule of table 10 is to the influence of adjuvant arthritis rats T lymphproliferation response (X ± S)
*Compare with the normal control group P＜0.01,
ΔCompare with model group P＜0.05.
The clear ruton arthralgia eliminating granule of table 11 is to the influence of adjuvant arthritis rats bone-marrow-derived lymphocyte breeder reaction (X ± S)
Compare with the normal control group * P＜0.01,
ΔCompare with model group P＜0.05.
By table 10,11 results as can be known, model group and normal control group comparison ConA, the inductive respectively lymphopoiesis ability of LPS obviously increase, clear three dosage groups of ruton arthralgia eliminating granule T, bone-marrow-derived lymphocyte multiplication capacity obviously reduce, relatively there were significant differences with model group.
2.3.5 discuss
This experimental result shows that clear three dosage groups of ruton arthralgia eliminating granule have the obvious suppression effect to the inductive lymphopoiesis of ConA, compares with model group, and there was a significant difference.In addition, the clear big or middle dosage group of ruton arthralgia eliminating granule also has the obvious suppression effect to the inductive bone-marrow-derived lymphocyte propagation of LPS, reflected that clear ruton arthralgia eliminating granule has stronger regulating action to the strong excessively immunoreation of adjuvant arthritis rat, this may be one of action principle of ruton arthralgia eliminating granule treatment rheumatoid arthritis clearly, may be that this product is in vivo by to breeding hypertrophy immunologically competent cell such as B cell, T faster
HThe direct inhibition of cell, thus hyperfunction humoral immune reaction suppressed, comprise that the generation, alleviation or the blocking-up that suppress autoantibody are by the inflammatory process of organizing (as synovium of joint) due to the immunoreation.
2.4 clear ruton arthralgia eliminating granule is to adjuvant arthritis rats IL-1 and PGE
2Influence
2.4.1 the making of model, grouping and processing:
Get 40 of male rats, 160-200g, randomly draw 10 and only be injected in right back sufficient sole of the foot Intradermal with normal saline 0.05ml/, in addition 30 with Fu Shi (Freund ' s) Freund's complete adjuvant 0.05ml/ only (wherein containing bacillus calmette-guerin vaccine 7.5mg/ml) be injected in right back sufficient sole of the foot Intradermal, after causing a scorching week rat is divided into three groups at random, adds that the normal control group is 4 groups altogether.I.e. 1. normal control group: normal saline 10ml/kg; 2. model group: normal saline 10ml/kg; 3. clear ruton numbness I group 7.2g crude drug/kg; 4. clear ruton numbness II group 14.4g crude drug/kg.Each organizes gastric infusion 1 time every day, successive administration 21 days.
2.4.2 clear ruton arthralgia eliminating granule produces the influence of interleukin I (IL-1) to adjuvant arthritis rat abdominal cavity macrophage
1. IL-1 induces: the rat carotid artery blood-letting, give and to inject cold 1640 10ml that contain 10% calf serum in the SD rat abdominal cavity, get peritoneal fluid after gently rubbing abdominal part, centrifuge washing prepares cell monolayer (macrophage monolayer) with 24 well culture plates, every hole adds the 1ml culture fluid again, continues to put 5%CO
2, cultivated 24 hours in 37 ℃ ,-30 ℃ of preservations are to be measured.2. IL-1 determination of activity: use mouse thymocyte proliferation assay, get the C57BL/6 mouse thymus and prepare the individual cells suspension, adjusting cell concentration with the RPMI1640 culture fluid that contains 10% calf serum is 2 * 10
7Individual/ml, add the ConA of 3 μ g/ml, mixing adds in 96 well culture plates as early as possible rapidly, and every hole 0.1ml contains cell 2 * 10
6Individual.Before adding the ConA-thymocyte cell, earlier the every hole of testing sample is added 0.1ml, put 5%CO
2, cultivated 60 hours in 37 ℃, every hole adds 0.2 μ ci
3H-TdR continues to cultivate 12 hours, and collecting cell is measured
3H-TdR mixes the cpm value, the results are shown in Table 12.
The clear ruton arthralgia eliminating granule of table 12 is to adjuvant arthritis rat abdominal cavity macrophage
The influence of generation interleukin I (IL-1) (x ± S)
* compare with the normal control group P＜0.05 * * P＜0.01
The Δ ΔCompare with model group P＜0.01
Table 12 is the result show: clear each dosage group of ruton numbness all can obviously reduce the level that adjuvant arthritis rat abdominal cavity cell produces interleukin I, and is remarkable with the model group comparing difference.
2.4.3 clear ruton arthralgia eliminating granule is to the plain E of adjuvant arthritis rat prostate
2(PGE
2) influence
The rat carotid artery blood-letting is with 2%EDTA-Na
2Anticoagulant, separated plasma is measured prostaglandin E with FMJ-182 radioimmunity gamma counter
2(PGE
2), the results are shown in Table 13.
The clear ruton arthralgia eliminating granule of table 13 is to adjuvant arthritis rat plasma prostaglandin E
2(PGE
2) influence (x ± S)
* compare with the normal control group P＜0.05 * * P＜0.01
The Δ ΔCompare with model group P＜0.01
Table 13 is the result show: clear each dosage group of ruton arthralgia eliminating granule all can obviously reduce adjuvant arthritis rat plasma PGE
2Value is remarkable with the model group comparing difference.
2.4.4 discuss
Cytokine interleukin-1 (IL-1) is closely related with rheumatoid arthritis.IL-1 obviously increases in the patient with rheumatoid arthritis whole blood, can detect highly active IL-1 in the inflammatory synovial fluid.It is mainly produced by mononuclear phagocyte, and complicated enlarge-effect is arranged in immunity and inflammatory reaction, and the energy activated lymphocyte stimulates the B cell to produce the antibody increase, can also promote the fibroblast hypertrophy, induces prostaglandin E
2Generation with collagenase, cause arthritis, the destruction of cartilaginous tissue, the while can strengthen the activity of osteoclast, promote decalcification of bone, cause osteoporosis, bone destruction stimulates vascular endothelial cell proliferation, increase the adhesion of PA and neutrophilic granulocyte to blood vessel wall, make vascular damaged, thicken, thrombosis increases the weight of joint injury.This experimental result shows: dosage and the heavy dose of group of IL-1 level that can significantly reduce the peritoneal macrophage generation of adjuvant arthritis rats in the clear ruton numbness illustrate that it has the unusual effect that produces of cytokine that suppresses.
Prostaglandin E
2Be a kind of important inflammatory mediator, mainly produce by macrophage.It is not only closely related with symptoms such as inflammatory reaction such as contrafluxion, edema and pain, and the destruction of known and sclerotin and repair relevant, the PGE of high concentration
2Osseous tissue is absorbed destroy increases, and is the another factor that promotes bone and destruction of joint.This experimental result points out in the clear ruton numbness dosage and heavy dose of group can obviously reduce adjuvant arthritis rats blood plasma PGE
2Value shows that it produces, reduces IL-1 unusually with inhibition IL-1 and induces joint and muscle PGE
2Synthetic relevant.
Infer thus, reduce IL-1 and PGE
2Level is the main pharmacological basis that rheumatoid arthritis is treated in replenishing YIN and removing heat, the ruling by law of a surname's numbness collateral dredging, alleviates arthropathy thereby play, and stops the effect of bone destruction generation, development.
Other experimental result also points out the big or middle dosage group of clear ruton arthralgia eliminating granule can reduce blood stasis rat whole blood viscosity, plasma viscosity and packed cell volume; Clear ruton arthralgia eliminating granule can obviously reduce adjuvant arthritis rats blood plasma thromboxane B
2(TXB
2), tumor necrosis factor (TNF) level; Suppress synovial cell's TNF secretion; Obviously improve the activity of body endogenous antioxidase SOD, reduce the content of serum levels of nitric oxide (NO).
In sum, clear ruton arthralgia eliminating granule has anti-inflammatory and antalgic, regulates immunologic derangement, antioxidation, anti-Gao Ning, suppress multiple pharmacotoxicological effect such as granulation tissue hyperplasia, for the clinical practice of replenishing YIN and removing heat, a surname's numbness collateral dredging method and square medicine provides objective basis.
(4) embodiment four: clinical trial
Adopt the table of random number method that 118 routine patient with rheumatoid arthritis are divided into ruton arthralgia eliminating granule group (being called for short the treatment group) and Glucosidorum Tripterygll Totorum group (abbreviation matched group) clearly at random, wherein 63 examples are organized in treatment, matched group 55 examples.Clinical observation the variation of lab index such as cardinal symptom sign and rheumatoid factor, erythrocyte sedimentation rate, c reactive protein, immunoglobulin, t lymphocyte subset group before and after two groups of treatments.
1, Therapeutic Method
(1) treatment group: with clear ruton arthralgia eliminating granule (every bag 5g contains crude drug 29g), each 1 bag, 3 times on the 1st, warm boiled water.
(2) matched group: use Glucosidorum Tripterygll Totorum, each 20mg, 2 ~ 3 times on the 1st, oral.
(3) course of treatment: two groups was 1 course of treatment with 3 months all.
2, include standard in
Be diagnosed as quasi-wind gateway, Chinese medical discrimination and belong to being in hospital and the outpatient of deficiency of YIN network heat syndrome, can include the test case in.
3, therapeutic outcome
Curative effect relatively sees the following form:
Treatment group and matched group curative effect are relatively
It is as shown in the table, and treatment group clinical cure rate is 9.52%, and the clinical cure obvious effective rate is 38.10%, and total effective rate is 90.48%; Matched group is respectively 0.00%, 20.00%, 83.64%.Check through Ridit for two groups, difference has significance (P＜0.05), and the curative effect of treatment group is better than matched group; The clinical cure obvious effective rate of wherein treatment group is apparently higher than matched group (P＜0.05).
Clinical observation result shows: the treatment group improve joint function disturbance, articular pain, morning deadlock and both hands grip, 15 meters cardinal symptom signs such as walking time aspect, the effect of treatment group is better than matched group (P＜0.05 or P＜0.01); At the immunoglobulin (IgG, IgA, IgM) that reduces rheumatoid factor (RF) titre, erythrocyte sedimentation rate (ESR), c reactive protein (CRP) and increase unusually, adjust helper T lymphocyte (CD4
+) and suppressor T lymphocyte (CD8
+) aspects such as ratio also be better than matched group (P＜0.05 or P＜0.01).Drug safety is observed, and does not see apparent side effect after the patient takes medicine, and treatment before and after look liver, renal function no abnormality seen change.The untoward reaction of aspects such as gastrointestinal tract, liver, blood, reproductive system appears in the Glucosidorum Tripterygll Totorum matched group.Confirm that clear ruton arthralgia eliminating granule has good efficacy to rheumatoid arthritis deficiency of YIN network heat syndrome, and do not have obvious toxicity.
Claims (7)
1. clear ruton numbness preparation for the treatment of rheumatoid arthritis is characterized in that by the made medicament of following materials of weight proportions medicine:
The Radix Rehmanniae 10～25g, Caulis Sinomenii 10～25g, Herba Taxilli 10～25g, Herba Siegesbeckiae 10～25g,
Radix Notoginseng powder 2～6g, Bombyx Batryticatus(processed) 10～15g, Radix Tripterygii Wilfordii 5～15g, Caulis Trachelospermi 10～25g.
2. the clear ruton numbness preparation of treatment rheumatoid arthritis according to claim 1 is characterized in that described preparation is granule, capsule, tablet or water preparation.
3. method for preparing the described clear ruton numbness preparation of claim 1, concrete steps are:
(1) take by weighing eight flavor crude drug of ruton numbness preparation clearly, Radix Notoginseng powder is broken into superfine powder, standby; All the other Radix Rehmanniae 7 flavors decoct with water;
(2) after the merging decoction liquor, microfiltration, filtrate decompression thin film concentration;
(3) concentrated solution is spray dried to dry powder;
(4) mixing behind the dry powder adding Radix Notoginseng superfine powder;
(5) add appropriate amount of auxiliary materials, mixing, dry granulation, packing, promptly.
4. the method for the clear ruton numbness of preparation according to claim 3 preparation is characterized in that decocting twice in step (1), and 11 times of water gagings decocted 1.5 hours for the first time, and 7 times of water gagings decocted 1 hour for the second time.
5. the method for the clear ruton numbness of preparation according to claim 3 preparation is characterized in that the microfiltration in step (2) is to be the inorganic ceramic film of 0.2 μ m with the aperture, and filtrate is concentrated into relative density 1.08～1.10.
6. the method for the clear ruton numbness of preparation according to claim 3 preparation is characterized in that in step (3) 170 ℃ of spray-dired inlet temperature, 70 ℃ of leaving air temps.
7. the method for the clear ruton numbness of preparation according to claim 3 preparation is characterized in that at the adjuvant described in the step (5) be dextrin and stevioside.
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| CN100361687C (en) * | 2005-11-22 | 2008-01-16 | 蓝子花 | Collateral-flow-activating pain-relieving medicine of Radix Asteris Scabri |
| CN101926926B (en) * | 2010-09-17 | 2012-07-04 | 湖南湘泉制药有限公司 | Traditional Chinese medicinal preparation for treating rheumatic arthritis and chronic infectious arthritis |
| CN103933299A (en) * | 2014-05-15 | 2014-07-23 | 李茂训 | Chinese herbal preparation for treating rheumatic arthritis |
| CN115581724A (en) * | 2022-10-20 | 2023-01-10 | 广州百奥格林生物科技有限公司 | Preparation method and system of traditional Chinese medicine compound preparation for treating rheumatoid arthritis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1196254A (en) * | 1998-05-05 | 1998-10-21 | 胡晓斌 | Pill for treating arthritis and its compounding method |
| CN1273834A (en) * | 2000-02-22 | 2000-11-22 | 陈永贵 | Chinese medicine for treating rheumatism |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1196254A (en) * | 1998-05-05 | 1998-10-21 | 胡晓斌 | Pill for treating arthritis and its compounding method |
| CN1273834A (en) * | 2000-02-22 | 2000-11-22 | 陈永贵 | Chinese medicine for treating rheumatism |
Non-Patent Citations (2)
| Title |
|---|
| 万节通痹方治疗类风湿性关节炎130例. 史建功.北京中医，第2期. 1988 * |
| 痹愈汤为主综合治疗类风湿性关节炎100例观察. 李锡涛等.中国中西医结合杂志，第13卷第2期. 1993 * |
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