CN1203788A - Therapeutic agent for rheumatic disease comprising nonsteroidal anti-inflammatory drug and phenylpropionic acid derivative - Google Patents
Therapeutic agent for rheumatic disease comprising nonsteroidal anti-inflammatory drug and phenylpropionic acid derivative Download PDFInfo
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- CN1203788A CN1203788A CN98103148.XA CN98103148A CN1203788A CN 1203788 A CN1203788 A CN 1203788A CN 98103148 A CN98103148 A CN 98103148A CN 1203788 A CN1203788 A CN 1203788A
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Abstract
An object of the present invention is to find a novel usefulness of 3-[1-[6-(4-methoxyphenyl)hex-5E-enyl]oxy-3-(4-carboxybutyl) oxybenzen-2-yl]propionic acid or a salt. The present invention relates to a therapeutic agent for rheumatic disease comprising a combination of a nonsteroidal anti-inflammatory drug with 3-[1-[6-(4-methoxyphenyl)hex-5E-enyl]oxy-3-(4-carboxybutyl)oxybenzen-2-yl]propionic acid or a salt thereof. Both components in this combination complement and/or potentiate their actions each other. The nonsteroidal anti-inflammatory drug is preferably diclofenac or a salt thereof.
Description
The present invention relates to contain nonsteroidal anti-inflammatory agent and 3-[1-[6-(4-methoxyphenyl) oneself-the 5E-thiazolinyl] oxygen base-3-(4-carboxylic butyl) oxygen base benzene-2-yl] the rheumatism therapeutic agent of propanoic acid or its salt.
Rheumatism is a kind of plain stubborn chronic inflammatory disease, and synovium of joint is the main damage position of this disease, still, people to the cause of this disease also and not really clear, rheumatism has multiple reveal any symptoms.A pathology characteristic of rheumatism is the improper hypertrophy of synovial membrane and the destruction of subsequently cartilage and skeleton being caused.The Therapeutic Method of rheumatism mainly is a Drug therapy, and therefore, with regard to medicine, steroid class medicine and nonsteroidal anti-inflammatory agent all have been used to treat the inflammation in the rheumatism.All become the medicine of treatment rheumatism owing to found the effect of immune factor in rheumatism, immunosuppressant, immunomodulator etc. not long ago.In addition, people also attempt multiple medicine is used in combination, and the purpose of this trial is to reduce each drug side effect and bring into play each curative effect of medication most possibly.
Now, also very active for medicine new role Study on Mechanism.Leukotriene B
4(LTB
4) antagonist is exactly one of them.As arachidonic metabolite in the 5-fat oxygen system, LTB
4Be considered to leukocyte function is produced important function, also have inflammation simultaneously and cause function.Particularly, it has very strong migration, chemotaxis, gathering, activation oxygen generates and discharge the ability that activates oxygen to leukocyte, in addition, and LTB
4By improve leukocyte on hemangioendothelioma (hemangioendothelial) cell tack and therefore vasoactive endothelioma (hemangioendothelium).On the other hand, there is report to think, the LTB in rheumatisant's joint fluid
4Content increases, simultaneously, and LTB
4Also can bring out the generation from il-1 among rheumatisant's the synovial cell of cultivation, wherein this synovial membrane cultured cell derives from rheumatisant (Rhumachi, 31,762 (1991)), and other has reported in literature, works as LTB
4During minimizing, diseases such as rheumatism, inflammatory bowel disease can improve (Exp.Opin.Invest.Drugs, 5,73-77 (1996)).
In publication number is the Japan special permission communique of 7-39369, disclose the 3-[1-[6-shown in the logical formula I (4-methoxyphenyl) oneself-the 5E-thiazolinyl] oxygen base benzene-3-(4-carboxylic butyl) oxygen base benzene-2-yl] propanoic acid (after this, to abbreviate " The compounds of this invention " as), have found that this chemical compound has LTB
4Antagonism also can effectively prevent and/or treat diseases such as multiple for example allergic dermatitis, rheumatism, gout, psoriasis, arthritis, trichophytosis and myocardial infarction.Other has report to claim that The compounds of this invention can competitive inhibition LTB
4Combine (prostaglandin, 44, the 261-275 (1982)) of bind receptor and human body neutrophilic leukocyte also shows immunosuppressive activity (today, surgery Surg.Today 26,419-426 (1996)) to the rat liver allotransplant.
In addition, LTB
4The research that receptor antagonist is used in combination with other kind medicines is also very various.For example, that had reported already has: coupling collar alkyl carboxylic acid derivative and nonsteroidal anti-inflammatory agent are to the arthritic action activity of bringing out property of collagen protein (rheumatic arthritis Arthritis Rheum, 39,515-521, (1996)), 1-benzopyran derivatives and COX-2 inhibitors conjugate are to the arthritic effect of bringing out property of collagen protein (WO 96/41645) and pyridine substituted benzyl alcohol derivant and nonsteroidal anti-inflammatory agent conjugate effect (the Japanese communique translation of PCT (public table) to the mating type experimental rat model of asthma, 7-505,401).
Yet not combining with nonsteroidal anti-inflammatory agent about The compounds of this invention so far is used for the treatment of the report of effect.
Therefore, (this chemical compound not only has LTB to The compounds of this invention
4The receptor antagonist effect and have immunosuppressive activity) the new purposes that is used in combination with nonsteroidal anti-inflammatory agent finds very interesting.
The inventor focuses on the combination of Therapeutic Method and the further investigation The compounds of this invention and the nonsteroidal anti-inflammatory agent of rheumatism.Utilize animal model to investigate medicine to the existing report of the several different methods of rheumatism effect.They are for example: the method for bringing out property of collagen protein arthritis model (natural Nature, 283,666-668 (1980); Proc.Natl.Acad.Sci.USA, 92,517-521 (1995)), method (rheumatism yearbook Ann.Rheum Dis., 15, the 379-380 (1956) of bringing out property of adjuvant arthritis model; Britain pharmacology magazine Br.J.pharmcol, 21,127-136 (1963)) etc.Because rheumatism is attended by inflammation and hydrarthrosis, utilize bringing out property of zymosan edema model as also existing report (Agents Actions, 32, the 119-121 (1991)) of the test method of acute inflammation model.Similarly, the effect to rheumatism among the present invention also takes above-mentioned animal model to measure.After this detailed test method of embodiment and result of the test prove that all The compounds of this invention can produce significant inhibition activity to test model with being used in combination of nonsteroidal anti-inflammatory agent.In addition, the effect that is produced be synergism and be The compounds of this invention and nonsteroidal anti-inflammatory agent when using separately can not reckon with.These results clearly show: the conjugate of The compounds of this invention and nonsteroidal anti-inflammatory agent is highly effective rheumatism therapeutic agent.Therapeutic agent of the present invention is all very effective for the treatment and the prevention of rheumatism.
Accompanying drawing 3 is the bone injury scoring diagrams in bringing out property of the type arthritis mouse model.In the accompanying drawing, A represents to accept The compounds of this invention (100mg/kg) and diclofenac sodium (3mg/kg) are subjected to the examination group in conjunction with administration result of the test (meansigma methodss of 7 routine animal subjects).B and C represent the individually dosed result of the test (meansigma methods of 9 routine animal subjects under each dosage) that is subjected to the examination group of The compounds of this invention (dosage is respectively 100mg/kg and 200mg/kg).D represents the individually dosed result of the test (9 routine meansigma methods) that is subjected to the examination group of diclofenac sodium (3mg/kg).E represents the result of the test (blank group, the meansigma methods of 9 examples) of not administration group.
Accompanying drawing 4 (a) and (b) the diurnal variation diagram of claw volume in expression adjuvant the bringing out property rat model of arthritis.Fig. 4 a is the long-pending change diagram of left back corpus unguis and the long-pending variation diagram of the right back corpus unguis of Fig. 4 b.In the accompanying drawings, o represents to accept The compounds of this invention (100mg/kg) and diclofenac sodium (1mg/kg) result of the test (7 routine meansigma methods) in conjunction with the administration group, represents to give separately the result of the test (8 routine meansigma methods) that The compounds of this invention (100mg/kg) is subjected to the examination group, △ represents to give separately the result of the test (8 routine meansigma methods) that diclofenac sodium (1mg/kg) is subjected to the examination group, ● represent the result of the test of not administration group (blank group, 8 routine meansigma methodss).
Accompanying drawing 5 (a) and (b) the diurnal variation diagram of claw volume in expression adjuvant the bringing out property rat model of arthritis.Fig. 4 a is the long-pending variation diagram of left back corpus unguis and the long-pending variation diagram of the right back corpus unguis of Fig. 4 b.In the accompanying drawings, o represents to accept The compounds of this invention (100mg/kg) and loxoprofen (3mg/kg) result of the test (8 routine meansigma methods) in conjunction with the administration group, represents to give separately the result of the test (8 routine meansigma methods) that The compounds of this invention (100mg/kg) is subjected to the examination group, △ represents to give separately the result of the test (8 routine meansigma methods) that loxoprofen (3mg/kg) is subjected to the examination group, ● represent the result of the test of not administration group (blank group, 8 routine meansigma methodss).
The present invention relates to contain nonsteroidal anti-inflammatory agent and 3-[1-[6-(4-methoxyphenyl) oneself-the 5E-thiazolinyl] oxygen base-3-(4-carboxylic butyl) oxygen base benzene-2-yl] the rheumatism therapeutic agent of conjugate of propanoic acid (The compounds of this invention) or its salt, and relate in particular to and be characterised in that above-mentioned two kinds of medicines have and complement each other and/or mutual synergistic rheumatism therapeutic agent.
In the treatment of rheumatism, nonsteroidal anti-inflammatory agent and The compounds of this invention both can have been made same dosage form administration, also can be about to each preparation and merge administration with the form administration of independent preparation.
The compounds of this invention can be the form of salt.Salt of the present invention there is no other restrictions except that the requirement that should satisfy officinal salt, and can for example be: inorganic acid salt, for example hydrochloric acid, nitric acid or vitriolic salt; Alkali metal salt or alkali salt, for example sodium, potassium or calcium; Ammonium salt; And and organic base, for example salt of diethylamine or triethanolamine formation.The compounds of this invention also can be a hydrate.
The present invention is characterised in that and is used in combination nonsteroidal anti-inflammatory agent and The compounds of this invention and unrestricted to antiinflammatory pharmacopoeia class.Among the present invention, anti-inflammatory agent is known compound and can for example is diclofenac, loxoprofen, ketoprofen, ibuprofen, naproxen, indometacin and piroxicam.In them some be salt for example sodium salt but repeat no more in this manual into salt except as otherwise noted.Sometimes, nonsteroidal anti-inflammatory agent of the present invention comprises so-called " prodrug ".
Suitable pharmaceutical preparation of the present invention can be the same preparation that contains nonsteroidal anti-inflammatory agent and The compounds of this invention, also can make different separately dosage forms.Preparation technique need not special requirement and can utilize the several different methods preparation.The dosage form example comprises the preparation of tablet, capsule, powder, granule and local injection, liquid preparation for external application and liniment and other generals and local administering mode.
When making independent preparation, nonsteroidal anti-inflammatory agent and The compounds of this invention also can adopt known technology.For example, with Japanese patent laid-open publication gazette 7-39, disclosed preparation is as the preparation of the commercially available anti-inflammatory agent product of The compounds of this invention preparation as nonsteroidal anti-inflammatory agent in 369.When preparation nonsteroidal anti-inflammatory agent and The compounds of this invention, can adopt said method equally.For example, the preparation solid dosage forms is tablet, capsule, powder and granule for example, can adopt in the preparation if desired: diluent, for example lactose, crystalline cellulose and starch; Lubricant, for example magnesium stearate and Talcum; Binding agent, for example hydroxypropyl cellulose and polyvinylpyrrolidone; Disintegrating agent, for example hydroxypropyl emthylcellulose of carboxymethylcellulose calcium and rudimentary replacement; And coating materials, for example hydroxypropyl emthylcellulose, macrogel and polyorganosiloxane resin.
Some examples of preparation can be referring to the following examples (example of formulations) but the present invention is not limited to described example of formulations.
The used dosage of nonsteroidal anti-inflammatory agent of the present invention and The compounds of this invention was decided with patient's symptom, age etc., and usually The compounds of this invention be administered once every day or for several times and daily dose between 1-1,000mg.Preferred daily dose is between 10-500mg, more preferably between 50-300mg.Non-steroid medicine dosage is decided with medicament categories, should decide and with situation adjustment such as diseases according to the dosage range of used anti-inflammatory agent itself usually, and its daily dose scope is between 1-1000mg and be administered once every day or for several times.Preferred daily dose is between 10-600mg.Particularly, use the daily dose under the diclofenac sodium situation to adjust between 75-100mg and according to works such as disease are certain.Other nonsteroidal anti-inflammatory agents can be determined according to same aim.Dosage also should change with dosage form.Dosage also should be suitable for The compounds of this invention preparation and nonsteroidal anti-inflammatory agent in conjunction with administration.When the present invention and nonsteroidal anti-inflammatory agent during with same preparation administration, preparation should select suitable drug ratios and daily dose in above-mentioned dosage range and the gained preparation is administered once every day or for several times.
Hereinafter pharmacological testing and example of formulations will be described.But, described embodiment only sharpen understanding the present invention with and be not to be used to limit protection domain of the present invention.The embodiment pharmacology test: (1) is to the arthritic effect of bringing out property of type:
The type arthritis model is the rheumatism sexually transmitted disease (STD) animal model that extensively adopts and relevant for utilizing this model as the research inhibiting report of LTB4 receptor antagonist (Proc.Natl.Acad.Sci.USA., 92,517-521 (1995)).
Now, measure The compounds of this invention according to the method identical and combine administration with nonsteroidal anti-inflammatory agent the arthritic effect of bringing out property of type with above-mentioned document.(test method)
With the dilute hydrochloric acid solution (4mg/ml) of cattle articular cartilage type be mixed and made into emulsion with the volume Freund's complete adjuvant.Is that the intradermal of mouse tail root is injected this emulsion and reached first sensitization (being equivalent to 200 a μ g type/mice) with the dosage of 100 μ l at DBA/1.First sensitization was injected 100 μ l above-mentioned emulsion in mouse tail root intradermal again and is carried out secondary sensitization after 21 day.
Prepare 0.5% suspension liquid of carboxyl methyl cellulose of The compounds of this invention and 1% methylcellulose suspension of nonsteroidal anti-inflammatory agent and also will test suspension from first continuous dosage 1 oral administration every day of sensitization beginning the previous day with the 10ml/kg body weight.
The following swelling phenomenon of erythema to show effect to occur at joint part as arthritic beginning of conclusive evidence.Be the evaluation arthritis order of severity, come total score value to scoring of Mus pawl arthritis rank and four paws as the arthritis score value according to following standards of grading.Other standards of grading of arthritis level:
0: no change
1: slight swelling that can observe and pale red speckle
2: slight swelling and the erythema that can observe
3: serious swelling that can observe and erythema
4: serious swelling that is attended by the bone erosion and the erythema that can observe
Then, secondary sensitization was carried out the X-radiography to the four paws joint after 26 days.Examine under a microscope each claw and according to following standards of grading evaluate the bone injury degree and with total score value of four paws as the bone injury score value.Bone injury rank standards of grading:
0: no change
1: the 1 phalanges damage that can observe
2: the bone injury of 2 or the more fingers that can observe
3: bone injury (result) takes place in whole joint
In 1 example of result of the test, merge the diclofenac sodium (3mg/kg) that gives The compounds of this invention (100mg/kg) and be used as nonsteroidal anti-inflammatory agent, the arthritis incidence rate is as shown in Figure 1; Accompanying drawing 2 is represented the variation diagram of arthritis score value, and accompanying drawing 3 is bone injury score value diagrams.
Be contrast, the result of the test that gives The compounds of this invention (100mg/kg and 200mg/kg), diclofenac sodium (3mg/kg) respectively separately and do not give any chemical compound (blank) group is shown in accompanying drawing 1-3.
At first, in the blank group of attached Fig. 1 and 2, observed the arthritis outbreak on the 3rd day after secondary sensitization, arthritic symptom all appears in beginning in the 7th day and all experimental animals.Subsequently, until the 21st day, arthritic symptom continued to worsen from secondary sensitization.
What be different from above-mentioned arthritis outbreak situation is, arthritic symptom do not occur in conjunction with the 14th day after secondary sensitization in the test that gives 100mg/kg The compounds of this invention and 3mg/kg diclofenac sodium, can think that therefore this administering mode can significantly delay the arthritis outbreak.Simultaneously the score value of arthritis attack degree also significantly improves, and does not all observe the serious edema that is attended by erythema after secondary sensitization on the 19th day.
Yet, give the improvement of arthritis score value in the The compounds of this invention 100mg/kg group and not obvious and the arthritis incidence rate approaches the mode of blank group separately.This trend just makes moderate progress after having used 200mg/kg dosage.
In giving 3mg/kg diclofenac sodium group separately, can be observed that arthritis score is improved but there is no effect delaying the arthritis outbreak.
Accompanying drawing 3 expression bone injuries suppress active, and the 100mg/kg The compounds of this invention is compared by the examination group with the 3mg/kg diclofenac sodium and shown significant bone injury inhibitory action with the blank group in conjunction with administration.On the contrary, give separately not observe any this inhibitory action in the 100mg/kg The compounds of this invention group, even 200mg/kg dosed administration group also is difficult to find this effect.In accepting 3mg/kg diclofenac sodium group separately, be very faint with comparing of two kinds of medicines merging administration groups though observed this effect of bone injury inhibitory action.
According to The above results, obviously The compounds of this invention and nonsteroidal anti-inflammatory agent can significantly be suppressed bringing out property of type arthritis and bone injury in conjunction with administration, in addition, to such an extent as to the gained result is so excellent reached The compounds of this invention or the individually dosed unexpected effect of nonsteroidal anti-inflammatory agent.(2) to the arthritic effect of bringing out property of adjuvant
Bringing out property of adjuvant arthritis model is the test model of widely used mensuration medicine to the joint action activity.Therefore, The compounds of this invention and nonsteroidal anti-inflammatory agent conjugate also utilize this model to measure.(test method)
It is (male that the liquid paraffin suspension (0.6mg/ μ l) of butanoic acid mycobacteria (adjuvant) is subcutaneously injected into the left back pawl of rat; 9 ages in week; Body weight is about 240g) to cause arthritis.Rose the suspension of testing compound with the oral dose administration of 0.5mg/100g body weight and every day 1 time on the 14th day adjuvant injection back, and wherein The compounds of this invention is suspended in 0.5% carboxymethyl cellulose and nonsteroidal anti-inflammatory agent is suspended in 1% the methylcellulose.
Equally, give study subject as blank with the same manner with the suspension that does not contain testing compound.(result)
After arthritis was brought out, claw edema occurs and volume increases.The 100mg/kg The compounds of this invention combines administration with 1mg/kg diclofenac sodium or 3mg/kg loxoprofen as typical nonsteroidal anti-inflammatory agent, and the change in volume of left back pawl is respectively shown in accompanying drawing 4a and 5a.Equally, arthritis is the symptom of general, and this symptom shows that not only the position of adjuvant injection also appears at right back pawl.Accompanying drawing 4b and 5b are the long-pending measurement results of right back corpus unguis.
As a comparison, The compounds of this invention and nonsteroidal anti-inflammatory agent result of the test individually dosed and the blank group will provide in respective drawings.
In addition, except recording above-mentioned result of the test, also carried out the histopathology detection.
Shown in accompanying drawing 4a and 5a, the left back pawl edema of bringing out property of adjuvant is basicly stable at the 14th day.The compounds of this invention and nonsteroidal anti-inflammatory agent in conjunction with the administration group in edema obviously suppressed.On the contrary, The compounds of this invention almost suppresses sign without any edema for individually dosed group.Though also can be observed edema for independent group, nonsteroidal anti-inflammatory agent suppresses effect, more remarkable in conjunction with the inhibitory action of administration group.In addition, shown in accompanying drawing 4b and 5b, edema appears in the 10th day right back pawl in adjuvant injection back.During the measuring claw volume, similar to left back pawl.The above results all shows the cooperative effect that is used in combination The compounds of this invention and nonsteroidal anti-inflammatory agent.
In addition, in histopathology check, using The compounds of this invention or nonsteroidal anti-inflammatory agent group separately and almost do not observe inhibitory action such as any bone injury, edema, then is obvious in conjunction with the inhibition activity of administration group.(3) to the effect of bringing out property of zymosan claw edema
Rheumatism often is attended by inflammation, can utilize animal model to test LTB
4Receptor antagonist is to the action and efficacy of this inflammation, and bringing out property of zymosan claw edema model is known test method (medicament and effect, Agents Actions, 32,119-121 (1991)).
Therefore, can study the action effect that The compounds of this invention and nonsteroidal anti-inflammatory agent are used in combination according to the test method of putting down in writing in the above-mentioned document.
Test is carried out according to the methods below.
The salt water slurry (2%) of zymosan is subcutaneously injected into the left back claw of rat position bringing out edema with the dosage of 100 μ l, and left back corpus unguis is long-pending promptly to begin to measure before injection and carries out equally in a period of time after injecting zymosan with the plethysmometer.Testing compound was an oral administration in preceding 1 hour at the injection zymosan.
The action and efficacy of testing compound use with zymosan injection before to compare the claw change in volume be that index is passed judgment on.
The result shows that The compounds of this invention and nonsteroidal anti-inflammatory agent are more remarkable than the inhibitory action that gives The compounds of this invention or nonsteroidal anti-inflammatory agent separately in conjunction with administration.[example of formulations]
The employing conventional method is mixed following component and is filled in the capsule.1) diclofenac sodium 25g The compounds of this invention 50g lactose 150g diclofenac sodium 3g The compounds of this invention 100g lactose 150g2)
Required capsule preparations can prepare with the variation of each amounts of components ratio.Can adopt other nonsteroidal anti-inflammatory agent to replace diclofenac sodium to prepare similar capsule equally.
According to above-mentioned pharmacological tests, can think that nonsteroidal anti-inflammatory agent and The compounds of this invention or its salt binding use to treat rheumatism very effectively.
Claims (3)
1. contain nonsteroidal anti-inflammatory agent and 3-[1-[6-(4-methoxyphenyl) oneself-the 5E-thiazolinyl] oxygen base-3-(4-carboxylic butyl) oxygen base benzene-2-yl] the rheumatism therapeutic agent of propanoic acid or its salt.
2. contain nonsteroidal anti-inflammatory agent and 3-[1-[6-(4-methoxyphenyl) oneself-the 5E-thiazolinyl] oxygen base-3-(4-carboxylic butyl) oxo time benzyl-2-yl] the rheumatism therapeutic agent of propanoic acid or its salt, wherein acting as of each medicine replenished and/or collaborative each other.
3. rheumatism therapeutic agent according to claim 1 and 2, anti-inflammatory agent wherein are diclofenac sodium or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98103148.XA CN1203788A (en) | 1997-06-18 | 1998-06-17 | Therapeutic agent for rheumatic disease comprising nonsteroidal anti-inflammatory drug and phenylpropionic acid derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP160801/97 | 1997-06-18 | ||
| CN98103148.XA CN1203788A (en) | 1997-06-18 | 1998-06-17 | Therapeutic agent for rheumatic disease comprising nonsteroidal anti-inflammatory drug and phenylpropionic acid derivative |
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| Publication Number | Publication Date |
|---|---|
| CN1203788A true CN1203788A (en) | 1999-01-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98103148.XA Pending CN1203788A (en) | 1997-06-18 | 1998-06-17 | Therapeutic agent for rheumatic disease comprising nonsteroidal anti-inflammatory drug and phenylpropionic acid derivative |
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| Country | Link |
|---|---|
| CN (1) | CN1203788A (en) |
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1998
- 1998-06-17 CN CN98103148.XA patent/CN1203788A/en active Pending
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