CN104887656A - Application of levodopa methyl ester hydrochloride to preparation of drugs for preventing and treating rheumatoid arthritis - Google Patents
Application of levodopa methyl ester hydrochloride to preparation of drugs for preventing and treating rheumatoid arthritis Download PDFInfo
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Abstract
The present invention provides a kind of application of L-dopa methyl ester hydrochloride in the drug of preparation prevention and treatment rheumatoid arthritis, and L-dopa methyl ester hydrochloride chemical structural formula is as follows:
. L-dopa methyl ester hydrochloride provided by the invention is definite to rheumatoid arthritis, provides strong foundation to develop L-dopa methyl ester hydrochloride for new drug.
Description
Technical field
The invention belongs to technical field of new application of medicine, relate to the medicinal usage of L-dopa methyl ester hydrochloride, be specifically related to the application of L-dopa methyl ester hydrochloride in the medicine of preparation control rheumatoid arthritis.
Background technology
Rheumatoid arthritis (Rheumatoid arthritis, RA) be a kind of common systemic autoimmune disease being feature with chronic, Progressive symmetric erythrokeratodermia, erosive arthritis, it mainly invades the Minor articulus such as hands, wrist, foot, also can involve after one's own heart, other organ or tissues such as lung, nervous system.RA basic pathological changes is joint synovitis disease, pannus formation, articular cartilage and sclerotin Progressive symmetric erythrokeratodermia destruction.Patient can have arthralgia, swelling, stiff and permanent joint destruction in the course of disease each stage, as failed to control in time, finally will cause patient articular's deformity and afunction, having very high disability rate, had a strong impact on the quality of life of patient.RA all can fall ill at each age level, and its onset peak age concentrates on 30 ~ 50 years old, and general female patient is more than male.According to statistics, this disease sickness rate in worldwide is about 0.5% ~ 1.0%, and in China, prevalence is about 0.32% ~ 0.36%.RA has become the one of the main reasons causing crowd's disability and deformity.
At present, RA therapeutic purposes are symptom management, make patient reach remission state as early as possible, improve function of joint, farthest keep patient's body normal function.The Therapeutic Principle of RA is early treatment, drug combination, therapeutic scheme individuation and functional exercise.Treatment clinically for RA is based on Drug therapy, mainly comprises NSAID (non-steroidal anti-inflammatory drug), improves the antirheumatic of the state of an illness, biological preparation, glucocorticoid and plant amedica preparation etc.Although the symptom of patient RA obtains obvious alleviation after treatment, prognosis is also significantly improved, and is still faced with the problems such as the state of an illness is easy repeatedly, adverse effect, drug resistance, therefore finds new RA medicine tool and be of great significance.
L-dopa methyl ester hydrochloride (LDME), chemical name is L-DOPA methyl ester hydrochloric acid, and its molecular formula is C10H13NO4.HCL, and molecular weight is 247.68, CAS No. is 1421-65-4, and structure is as shown in formula I:
LDME is the prodrug of levodopa, after being hydrolyzed to levodopa, enters maincenter by blood brain barrier, changes into dopamine through DOPA decarboxylase effect, clinically for improving Parkinsonian symptoms.LDME is soluble in water, easily makes various peroral dosage form and injection administration, absorbs fast, 7-8 minute blood drug level peaking, more rapid-action than levodopa, and curative effect certainly.Animal experiment study showed that LDME also had therapeutical effect to amblyopia in recent years.There is no the relation of research LDME and rheumatoid arthritis at present, the present invention comes therefrom.
Summary of the invention
the technical problem solved:for the existing shortage studying the relation of LDME and rheumatoid arthritis, the invention provides the application of a kind of L-dopa methyl ester hydrochloride in the medicine of preparation control rheumatoid arthritis, for control rheumatoid arthritis provides a kind of new way.
technical scheme:the application of L-dopa methyl ester hydrochloride in the medicine of preparation control rheumatoid arthritis, L-dopa methyl ester hydrochloride chemical structural formula is as follows:
。
Described pharmaceutical composition comprises the L-dopa methyl ester hydrochloride of pharmaceutical effective dose and pharmaceutically acceptable carrier.
Described is prepared into the pharmaceutical preparation being applicable to gastrointestinal tract or parenteral administration by L-dopa methyl ester hydrochloride.
Described being prepared into by L-dopa methyl ester hydrochloride is applicable to gastrointestinal pharmaceutical preparation, and its dosage form is conventional tablet, capsule, controlled release preparation or slow releasing preparation.
In the described pharmaceutical preparation be prepared at L-dopa methyl ester hydrochloride, L-dopa methyl ester hydrochloride content is in the formulation 1wt% ~ 99wt%.
In the described pharmaceutical preparation be prepared at L-dopa methyl ester hydrochloride, L-dopa methyl ester hydrochloride content is in the formulation 10wt% ~ 90wt%.
The preparation method of described pharmaceutical preparation for L-dopa methyl ester hydrochloride is directly made preparation, or respectively or/and make preparation after adjuvant mixing, then carries out packing and get final product.
The dosage of described pharmaceutical composition changes according to the dosage form difference of administration object, route of administration or medicine, but to ensure that this pharmaceutical composition can reach premised on effective blood drug level in mammalian body.
L-dopa methyl ester hydrochloride (LDME), its molecular formula is C
10h
13nO
4.HCL, chemical name is L-DOPA methyl ester hydrochloric acid, and molecular weight is 247.68, CAS No. is 1421-65-4, derives from Sigma-Aldrich Co.LLC. company.
Can technical solution of the present invention studies LDME by intraperitoneal injection method have therapeutical effect to collagen-induced method establishment rheumatoid arthritis mice (CIA), Simultaneously test tumor necrosis factor-alpha (TNF-α), the inflammatory Cytokines Expression changes such as Interleukin-1β (IL-1 β) and IL-6, to providing experimental basis for inquiring into LDME treatment rheumatoid arthritis.
The present invention is divided into 5 groups at random by 40 DBA/1j mices, i.e. normal group (Control), model group (Vehicle), positive controls (methotrexate, 2mg/kg; MTX), LDME high dose group and LDME low dose group, the dosage of LDME high dose group is the dosage of 100mg/kg, LDME low dose group is 25mg/kg.Press 100mg/kg and 25mg/kg successive administration in secondary immunity the previous day (the 20th day) respectively to the 70th day LDME group, MTX group presses 2mg/kg administration in every 2 days, Control and Vehicle group gives drinking water by 10ml/kg.Routine observation respectively organizes experiment mice ordinary circumstance, record mice vola thickness, arthritis score; Put to death animal in the 70th day for each group and retain serum and hindlimb joints specimen, respectively row iconography, histology and molecular Biological Detection.One factor analysis of variance is adopted to carry out statistical analysis to each group of data.
Result of the present invention shows, Control group mice is flexibly movable, and the mental status is good, and normally, joint motion freely for drinking-water and appetite.Vehicle group mice lethargy, drinking-water and appetite reduce, and joint motion has obvious obstacle, and the obvious enlargement of extremities joint, lasting edema, dermathemia, skin temperature rise, range of motion is little.The LDME low dose group mice mental status is general, drinks water and the situation of ingesting is better than Vehicle group, and joint motion is limited, and partial joint is red and swollen, and locomotor activity obtains part and recovers.LDME high dose group and MTX group mouse diet situation are significantly better than Vehicle group, and the mental status is better, and joint is slightly red and swollen, without obvious moving obstacle.Within 21st day, start swelling gradually after Vehicle group mice vola initial immunity, reach the highest to swelling degree when the 42nd day, compare with Control group, difference has statistical significance (p<0.05).LDME low dose group, the swelling of mice vola is made slow progress, and initial immunity is after the 42nd day, and mice vola swelling degree alleviates gradually, and when last is measured, the mice vola thickness that swells compares with Vehicle group, and difference has statistical significance (p<0.05).Vehicle group arthritis score peaked in the 42nd day; MTX group significantly reduces D38 days arthritis score; LDME high dose group and LDME low dose group significantly suppressed CIA mice arthropathy at the 36th, the 42nd day respectively.Micro-CT scanning result shows, LDME low dose group: bony surface is very crude, and joint space constriction is serious, and articulation structure destroys comparatively serious, and comparatively Vehicle group slightly takes a turn for the better; LDME high dose group and MTX group: bony surface is substantially complete, joint space is almost normal, and articulation structure is high-visible.Histological stain result display Control group articular cartilage queueing discipline, even dyeing; Articular surface is complete, and cartilage is pink light dyeing, and sclerotin is peony, and joint space is normal, and synovial tissue's structure is smooth, has no synovial hyperplasia and inflammatory cell infiltration phenomenon.Vehicle group main manifestations is: a large amount of inflammatory cell infiltration, appears in the remarkable hypertrophy of synovial tissue, new vessels showed increased; Chondrocyte arrangement disorder, articular cartilage and sclerotin are seriously damaged, and cartilage surface is crude uneven, and joint space disappears.LDME high dose group, LDME low dose group and MTX treatment group can alleviate above pathological change in various degree, show as the slight hypertrophy of synovial tissue, and inflammatory cell infiltration reduces, and new vessels reduces, and cartilage injury's degree obviously alleviates.ELISA result display LDME can reduce the content of TNF-α, IL-1 β and IL-6 in CIA mice serum, and pointing out the regulating action of inflammatory factor may be the important mechanisms that LDME treats rheumatoid arthritis.
This zoopery confirms that L-dopa methyl ester hydrochloride (LDME) has certain preventive and therapeutic effect to rheumatoid arthritis, destruction of joint and inflammatory reaction can be made to be inhibited, can be used as a kind of new tool of the pharmaceutical intervention of rheumatoid arthritis.
beneficial effect:the application of L-dopa methyl ester hydrochloride provided by the invention in the medicine of preparation control rheumatoid arthritis, has the following advantages:
1. L-dopa methyl ester hydrochloride has the purposes of high-efficiency prevention and control rheumatoid arthritis, can remarkable mitigation symptoms, as arthroncus, arthritis score, and can alleviate destruction of joint, reduce Secretion of Inflammatory Factors;
2. L-dopa methyl ester hydrochloride is definite to rheumatoid arthritis, provides strong foundation for L-dopa methyl ester hydrochloride being developed as new drug.
3. the present invention has excavated the new prospect in medicine of L-dopa methyl ester hydrochloride, has opened up a new medicinal applications; L-dopa methyl ester hydrochloride is that toxic and side effects is little, and Long-term taking medicine is without harm clinically for improving the common drug of Parkinsonian symptoms, taking convenience.
Accompanying drawing explanation
Fig. 1 is Control group, Vehicle group, MTX group, LDME high dose group, LDME low dose group small mouse hind leg vola varied in thickness figure.
Fig. 2 is Control group, Vehicle group, MTX group, LDME high dose group, LDME low dose group small mouse arthritis score figure.
Fig. 3 is Control group, Vehicle group, MTX group, LDME high dose group, LDME low dose group small mouse micro-CT testing result figure.
Fig. 4 is Control group, Vehicle group, MTX group, LDME high dose group, LDME low dose group small mouse knee joint histo pathological change figure.
Fig. 5 is Control group, Vehicle group, MTX group, LDME high dose group, LDME low dose group small mouse serum ELISA testing result figure.
Detailed description of the invention
embodiment 1
One, materials and methods
1. material
1.1 reagent and experimental facilities
1.1.1 primary drug and reagent
L-dopa methyl ester hydrochloride (LDME), dimethyl sulfoxine (DMSO), hydrogen peroxide, disodium EDTA dihydrate (EDTA) purchased from Sigma, the U.S.; Cattle II Collagen Type VI, incomplete Freund's adjuvant (IFA), complete Freund's adjuvant (CFA) purchased from Chondrex, the U.S.; Methanol, hydrochloric acid, glacial acetic acid, ammonia, dehydrated alcohol, 95% ethanol, paraformaldehyde are purchased from peak, Shanghai chemical reagent company limited; ColeShi haematoxylin dyeing liquid (normal dyeing), eosin stains liquid are purchased from Beijing Suo Laibao Science and Technology Ltd.; TNF-α, IL-1 β, IL-6 enzyme-linked immunosorbent adsorption test detection kit, purchased from Biosource, the U.S..
1.1.2 key instrument
Micro-CT(SkyScan 1176, Belgium), paraffin slicing machine (Leica 2135, Germany), roasting sheet machine (Leica 1120, Germany), paraffin wax embedding (BMJ-II, China, Changzhou), Axio imager.MI just putting microscope (Zeiss, Germany), microplate reader (Biotec, the U.S.), Sim-F140 ice machine (Sanyo, Japan), operating theater instruments be a set of etc.
1.2 laboratory animal
Male DBA/1j mice, 40, body weight 20-25g, 6-8 week age, purchased from Beijing HFK Bio-Technology Co., Ltd..Laboratory animal is all raised in University Of Suzhou SPF level experiment room, room temperature (23 ± 1) DEG C, relative humidity (55 ± 10) %, and throwing light in interval, freely ingests and drink water, and adaptability is raised after one week and used.
2. experimental technique
The foundation of 2.1 mouse collagen Induced Arthritis models and evaluation
2.1.1 the foundation of mouse collagen Induced Arthritis model
(1) preparation of emulsifying agent: be dissolved in the glacial acetic acid of 10 mM by a certain amount of cattle II type (CII) collagen, be configured to the solution that concentration is 2mg/mL, 4 DEG C of stirrings are spent the night.Mixed with completely not formula adjuvant (freurd incomplete adjuvant) equal-volume by consoluet collagen solution, use tee T the two to be mixed completely, make it fully emulsified, making containing collagen concentration is the Emulsion of lmg/mL.Emulsifying agent needs now with the current, and should be positioned on ice face in case temperature raises cause collagenous degeneration.
(2) mice is put into holder and expose tail, left hand pinches mouse tail root gently, and the right hand holds microsyringe at distance root of the tail portion 1.5-2.0cm place inserting needle on the lower, intradermal injection 100 μ L emulsifying agent.If there is emulsifying agent to overflow in bolus infusion processes, then new injection point should be selected to carry out supplementing the appropriate emulsifying agent of injection.
(3) first time inoculation gets the emulsifying agent booster injection of same dose once after 3 weeks.Note: the preparation of this emulsifying agent is cannotd be used up, and complete not formula adjuvant and collagen are mixed.
(4) after second time booster immunization, 4-5 days mices there will be redness in various degree, and within about 38 days, peak to initial immunity, within general about 45 days, Ke Da more than 95% becomes mould rate.
2.1.2 experiment grouping and administration
Random digits table all laboratory animals is adopted to be divided into 5 groups (often organizing 8), i.e. normal group (Control), model group (Vehicle), positive controls (methotrexate, 2mg/kg; MTX), LDME component is high (H-LDME) and low (L-LDME) two dosage groups, and its dosage is respectively 100mg/kg and 25mg/kg.100mg/kg and 25mg/kg successive administration is pressed respectively to the 70th day LDME group in secondary immunity the previous day (the 20th day), MTX group presses 2mg/kg administration in every 2 days, Vehicle group is raised through intraperitoneal injection of saline 0.1ml/kg/d, Control group mice routine, disregards.
2.1.3 the evaluation of mouse collagen Induced Arthritis model
(1) mice metapedes vola thickness measure: from D21, use the metapedes vola thickness of slide gauge to mice homonymy to measure, measure 2 times weekly, each repeated measure 3 times, averages.All measurements are by two experimenter's complete independentlies.
(2) arthritis and the scoring of swelling degree: from D21, mark to each group of rat articular swelling degree, evaluate and test 2 times weekly, each repeated measure 3 times, averages.Each arthropathy degree is evaluated by 5 grades of point systems, and each limbs best result is 4 points, and every mice is up to 16 points.Concrete standards of grading are as follows: 0 point: without red and swollen; 1 point: little toe joint mild redness; 2 points: toe joint and sufficient sole of the foot arthroncus; 3 points: the sufficient pawl swelling below ankle joint; 4 grades: the whole sufficient pawl comprising ankle joint all occurs swelling, and function completely loses.
2.3 collection of specimens
Mouse orbit venous plexus is taken a blood sample, and with orbital venous plexus blood collection method blood sampling 0.25ml before sacrifice, concrete grammar is as follows: get the capillary glass tube that internal diameter is 1.0-1.5mm, and with fractureing into the long capillary tube of 1-1.5cm before, 1% heparin solution soaks, and uses after dry.After left hand is fixing by mice, to lower compression cervical region both sides, the right hand holds capillary tube blood sampling, accesses in ready container.After blood sampling, gauze gently presses hemostasis.Specimen, with the centrifugal 10min of 3000g, obtains serum-70 DEG C preservation.
Mice joint specimen: each treated animal equal lumbar injection 10% chloral hydrate anesthesia, lie on the back extenal fixation on mice crosshead, open breast and expose heart, through apex of the heart heart catherization perfusion left, cut off right auricle, after ligation descending aorta, refrigerant liquid is flowed out in open normal saline flushing to right auricle, then pour into 4% neutral paraformaldehyde 200 ~ 300ml, to animal foot tic, hardening.Take out bilateral hind leg rapidly after perfusion, reject basis cranii attaching soft tissue, retain knee joint and toes joint ,-70 DEG C of preservations.
2.4 Micro-CT analyze
Within after initial immunity the 70th day, put to death mice, take out mice rear solid end, 10% paraformaldehyde adopts Micro-CT scanning (SkyScan 1076) to scan all specimen after fixing 48 hours, the parameters of scanning arranges as follows: spatial resolution 9 μm, voltage 70 kV, electric current 141 μ A, sweep time 1750ms, after having scanned, the software carried is utilized to analyze mouse ankle joint and build the three-dimensional reconstruction image of specimen.
2.5 histopathology histology
2.5.1 mice joint pathology microsection manufacture
(1) fixing, decalcification: D70 puts to death mice, and take out rear solid end, fix 48 hours with 4% paraformaldehyde, be then placed in 10%EDTA decalcifying Fluid decalcification 1 month, 2d changes liquid 1 time,
(2) dewater, waxdip: the specimen after decalcification is used running water 30-60min, then carries out dewatering, waxdip, idiographic flow is in Table:
(3) embed: embed on embedding machine, to press on flat for mice knee joint section at the bottom of embedded box and to be adjacent to, after paraffin, releasing wax stone, make solid wax stone.
(4) cut into slices, open up sheet, roasting sheet: the wax stone trimmed is cut into slices, with rotary microtome, sample is cut into the serial section that thickness is 4-5 μm, exhibition sheet machine water-bath exhibition sheet (water temperature 43 DEG C) is put into front, as far as possible smooth, non-wrinkled during exhibition sheet, with clean microscope slide list sheet, drag for after sheet completes section to be placed on roasting sheet machine and carry out roasting sheet (temperature 60 C) 4 hours, prevent bubble from producing.
2.5.2 Hematoxylin-eosin dyeing (H & E dyes)
H & E staining is the most frequently used colouring method of morphology, is also one of staining conventional in paraffin section technology simultaneously.The morphosis of various tissue or cell can be observed by this colouring method.
Experimental procedure:
Sheet 30min baked by (1) 60 DEG C of baking oven.
(2) paraffin section is placed in dimethylbenzene I, II, each 15min.
(3) dehydrated alcohol I, II, 95% ethanol I, II, each 5 minutes of 90% ethanol, 80% ethanol, 70% ethanol.
(4) haematoxylin dyeing 1-3min, tap water 1min.
(5) 1% acidic alcohols break up 20 seconds.
(6) 1% weak ammonia return blue 30 seconds, tap water 1min.
(7) eosin stains 3 minutes, washes 5min from the beginning.
(8) conventional dehydration, transparent (80% ethanol 5min, 90% ethanol 5min, 95% ethanol 5min, dehydrated alcohol 5min, transparent I 10min of dimethylbenzene, transparent II 10min of dimethylbenzene).
(9) neutral gum mounting.
(10) basis of microscopic observation Color: nucleus is in blue, and cytoplasm, connective tissue etc. take on a red color.
2.6 enzyme-linked immunosorbent assays (ELISA) detect TNF-α, IL-1 β and IL-6
ELISA detects TNF-α, IL-1 β and IL-6 in serum
.
With reference to ELISA kit description, concrete steps are as follows:
(1) gauge orifice 8 hole is set up, every Kong Zhongxian adds sample diluting liquid 100 μ l, first hole adds standard substance 100 μ l again, with pipettor sucking-off 100 μ l after mixing, move to the second hole, so repeatedly oppose and be doubly diluted to the 7th hole, finally, from the 7th hole, sucking-off 100 μ l discards, and makes it volume and is 100 μ l.8th hole is blank.
(2) application of sample: Zhong Mei hole, testing sample hole respectively adds supernatant 100 μ l, Sptting plate is placed in 37 DEG C × 120 min;
(3) with cleaning mixture, Sptting plate is fully washed 4 ~ 6 times, buckle dry on filter paper, add first antibody working solution 50ul in every hole, Sptting plate is fully mixed rearmounted 37 DEG C × 60 min.
(4) with cleaning mixture, Sptting plate is fully washed 4 ~ 6 times, buckle dry on filter paper, every hole adds enzyme labelled antibody working solution 100ul, Sptting plate is placed in 37 DEG C of 120 min;
(5) with cleaning mixture, Sptting plate is fully washed 4 ~ 6 times, buckle dry on filter paper, in every hole, add substrate working solution 100ul, be placed in 37 DEG C of dark place reaction 5 ~ 10 min;
(6) add the mixing of 50ul stop buffer in every hole, survey light absorption value by microplate reader at 450nM place;
(7) map on semilogarithmic paper with the OD value of standard substance 1000,500,250,125,62.5,31.25,15.625,0 pg/ml, draw standard curve; Testing index content in serum is gone out according to standard curve formula scales.
2.7 statistical analysis
Result data adopts SPSS11.0 statistical software to analyze, data mean ± standard deviation (
) represent, multiple-group analysis selects one factor analysis of variance (one-way ANOVA checks), compares between two under the neat condition of population variance, selects LSD and Dunnett-t method to analyze.P<0.05 is that difference has statistical significance.
Two, result
1. laboratory animal ordinary circumstance
Without dead mouse in experimentation.Control group mice is flexibly movable, and the mental status is good, and normally, joint motion freely for drinking-water and appetite.Vehicle group mice lethargy, drinking-water and appetite reduce, and joint motion has obvious obstacle, and the obvious enlargement of extremities joint, lasting edema, dermathemia, skin temperature rise, range of motion is little.The L-LDME group mice mental status is general, drinks water and the situation of ingesting is better than Vehicle group, and joint motion is limited, and partial joint is red and swollen, and locomotor activity obtains part and recovers.H-LDME group and MTX group mouse diet situation are significantly better than Vehicle group, and the mental status is better, and joint is slightly red and swollen, without obvious moving obstacle.
2. LDME is on the impact of CIA mice vola thickness
From after initial immunity the 21st day, each group of right side of mice metapedes is carried out to the measurement of vola thickness, measure 2 times weekly.Within 21st day, start swelling gradually after Vehicle group mice vola initial immunity, reach the highest to swelling degree when the 42nd day, compare with Control group, difference has statistical significance (p<0.05).LDME treatment group, the swelling of mice vola is made slow progress, and initial immunity is after the 42nd day, and mice vola swelling degree alleviates gradually, and when last is measured, the mice vola thickness that swells compares with Vehicle group, and difference has statistical significance (p<0.05).See Fig. 1.
3. LDME impact that CIA mouse arthritis is marked
After Vehicle group mice secondary immunity there is red and swollen, distortion in hindlimb joints, and arthritis score peaked in D42 days; MTX group significantly reduces D38 days arthritis score; LDME(high dose and low dosage) significantly suppress CIA mice arthropathy at D36, D42 respectively, compare with Vehicle group, difference has statistical significance (p<0.05).See Fig. 2.
4. LDME is on the impact of CIA mice destruction of joint
Micro-CT scanning result shows, Control group: bony surface is smooth, and joint space is normal, and articulation structure is complete, and breakoff phenomenon does not appear in sclerotin; Vehicle group: bony surface is uneven, articulation structure destroys serious, and joint space disappears completely; L-LDME group: bony surface is very crude, joint space constriction is serious, and articulation structure destroys comparatively serious, and comparatively model group slightly takes a turn for the better; H-LDME and MTX group: bony surface is substantially complete, joint space is almost normal, and articulation structure is high-visible.See Fig. 3.
5. each group mice joint tissue pathological change
Control group articular cartilage queueing discipline, even dyeing; Articular surface is complete, and cartilage is pink light dyeing, and sclerotin is peony, and joint space is normal, and synovial tissue's structure is smooth, has no synovial hyperplasia and inflammatory cell infiltration phenomenon.Vehicle group main manifestations is: a large amount of inflammatory cell infiltration, appears in the remarkable hypertrophy of synovial tissue, new vessels showed increased; Chondrocyte arrangement disorder, articular cartilage and sclerotin are seriously damaged, and cartilage surface is crude uneven, and joint space disappears.LDME and MTX treatment group can alleviate above pathological change in various degree, shows as the slight hypertrophy of synovial tissue, and inflammatory cell infiltration reduces, and new vessels reduces, and cartilage injury's degree obviously alleviates.See Fig. 4.
6. LDME is on the impact of CIA mice serum TNF-α, IL-1 β and IL-6
The content of Vehicle group mice serum TNF-α, IL-1 β and IL-6 is apparently higher than normal group, by table as seen after LDME treats, the content of H-LDME group IL-1 β and IL-6 obviously reduces, and TNF-α all significantly reduces in each treatment group, compare with Vehicle group, difference has statistical significance (p<0.05; See Fig. 5).The above results prompting may be the important mechanisms that LDME treats rheumatoid arthritis to the regulating action of inflammatory factor.
Conclusion: LDME significantly can reduce the content of TNF-α, IL-1 β and IL-6 in CIA mice serum, obviously suppresses CIA mouse arthritis disease, and significantly can reduce CIA mice inflamed joint destruction.LDME has obvious curative effect to CIA mice, and the Drug therapy for clinical rheumatoid arthritis provides new selection.
Claims (8)
1. the application of L-dopa methyl ester hydrochloride in the medicine of preparation control rheumatoid arthritis, L-dopa methyl ester hydrochloride chemical structural formula is as follows:
。
2. the application of L-dopa methyl ester hydrochloride according to claim 1 in the medicine of preparation control rheumatoid arthritis, is characterized in that described pharmaceutical composition comprises the L-dopa methyl ester hydrochloride of pharmaceutical effective dose and pharmaceutically acceptable carrier.
3. the application of L-dopa methyl ester hydrochloride according to claim 1 in the medicine of preparation control rheumatoid arthritis, is characterized in that described L-dopa methyl ester hydrochloride being prepared into the pharmaceutical preparation being applicable to gastrointestinal tract or parenteral administration.
4. the application of L-dopa methyl ester hydrochloride according to claim 3 in the medicine of preparation control rheumatoid arthritis, it is characterized in that described being prepared into by L-dopa methyl ester hydrochloride is applicable to gastrointestinal pharmaceutical preparation, its dosage form is conventional tablet, capsule, controlled release preparation or slow releasing preparation.
5. the application of L-dopa methyl ester hydrochloride according to claim 4 in the medicine of preparation control rheumatoid arthritis, it is characterized in that in the described pharmaceutical preparation be prepared at L-dopa methyl ester hydrochloride, L-dopa methyl ester hydrochloride content is in the formulation 1wt% ~ 99wt%.
6. the application of L-dopa methyl ester hydrochloride according to claim 5 in the medicine of preparation control rheumatoid arthritis, it is characterized in that in the described pharmaceutical preparation be prepared at L-dopa methyl ester hydrochloride, L-dopa methyl ester hydrochloride content is in the formulation 10wt% ~ 90wt%.
7. the application of L-dopa methyl ester hydrochloride according to claim 3 in the medicine of preparation control rheumatoid arthritis, it is characterized in that the preparation method of described pharmaceutical preparation is for directly to make preparation by L-dopa methyl ester hydrochloride, or respectively or/and make preparation after adjuvant mixing, then carry out packing and get final product.
8. the application of L-dopa methyl ester hydrochloride according to claim 3 in the medicine of preparation control rheumatoid arthritis, it is characterized in that the dosage of described pharmaceutical composition changes according to the dosage form difference of administration object, route of administration or medicine, but to ensure that this pharmaceutical composition can reach premised on effective blood drug level in mammalian body.
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| US20060173074A1 (en) * | 2004-11-10 | 2006-08-03 | Juha Ellmen | Treatment of restless legs syndrome |
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