CN103919776A - Pharmaceutical composition for treating arthritis - Google Patents
Pharmaceutical composition for treating arthritis Download PDFInfo
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- CN103919776A CN103919776A CN201410173902.5A CN201410173902A CN103919776A CN 103919776 A CN103919776 A CN 103919776A CN 201410173902 A CN201410173902 A CN 201410173902A CN 103919776 A CN103919776 A CN 103919776A
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- pharmaceutical composition
- acetaminophen
- arthritis
- tetrahydropalmatine
- treatment
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- 206010003246 arthritis Diseases 0.000 title claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 60
- AEQDJSLRWYMAQI-UHFFFAOYSA-N Tetrahydropalmatine Natural products C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims abstract description 28
- AEQDJSLRWYMAQI-KRWDZBQOSA-N tetrahydropalmatine Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3C[C@H]2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-KRWDZBQOSA-N 0.000 claims abstract description 28
- 229960005489 paracetamol Drugs 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims description 15
- UELPQYXGRIZTHA-XSEBJXQCSA-N rotundin Chemical compound C1[C@H](O)\C(C)=C/[C@H]2OC(=O)C(=C)[C@@H]2[C@H](OC(=O)C(\C)=C/C)C[C@@]2(COC(C)=O)O[C@@H]21 UELPQYXGRIZTHA-XSEBJXQCSA-N 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 6
- UELPQYXGRIZTHA-UHFFFAOYSA-N Rotundin Natural products CC=C(C)/C(=O)OC1CC2(COC(=O)C)OC2CC(O)C(=C/C3OC(=O)C(=C)C13)C UELPQYXGRIZTHA-UHFFFAOYSA-N 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 14
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- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
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- 230000002588 toxic effect Effects 0.000 abstract description 3
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 7
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- 210000002683 foot Anatomy 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 201000008482 osteoarthritis Diseases 0.000 description 3
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- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
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- 238000010168 coupling process Methods 0.000 description 2
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000008407 joint function Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 2
- 229960005249 misoprostol Drugs 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229930189907 rotundine Natural products 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 101100275473 Caenorhabditis elegans ctc-3 gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100168274 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-3 gene Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
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- 239000003146 anticoagulant agent Substances 0.000 description 1
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- 230000002917 arthritic effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
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- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
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- 229920000669 heparin Polymers 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
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- 210000001589 microsome Anatomy 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition for treating arthritis, belonging to the technical field of medicines. The pharmaceutical composition contains tetrahydropalmatine and acetaminophen, wherein the weight ratio of the tetrahydropalmatine to the acetaminophen is 1:(0.5-4). The most important advantage of the pharmaceutical composition is synergetic anti-inflammation, and simultaneously the dosage of the tetrahydropalmatine and the acetaminophen in independent use is reduced, so that the cost of medication for a patient is lowered, toxic and side effects of the acetaminophen are alleviated as well, and the safety of medication and the compliance of the patient are improved.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition for the treatment of of arthritis.
Background technology
Arthritis refers to the arthritis pathological changes being caused by inflammation, infection, wound or other factors, belong to rheumatism subject disease, comparatively common are osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and gouty arthritis, all can cause to some extent the obstacle of function of joint, and the course of disease is long, touching difficulty heals, and common trait is the chronic inflammatory disease process of carrying out sexual development.Main clinical manifestation is the symptoms such as arthralgia, arthroncus, joint function disturbance, is one of major reason disabling.According to statistics, global arthritic reaches 3.55 hundred million, and China's arthritis surpasses 100,000,000, and number is also in continuous increase.Arthritis has had a strong impact on patient's life, working and learning, so there is the exploitation of the arthritis treatment medicine of good result to have great importance.
For the arthritis cure method that also neither one is satisfied with, be all generally symptomatic treatment at present, alleviate arthralgia, improve range of motion, reduce joint function disturbance.Slight arthritis can be taked conservative treatment, for most of patients with osteoarthritis, slightly to moderate pain, can control by taking analgesic drug product, and these drug mains will comprise the NSAID (non-steroidal anti-inflammatory drug) such as acetaminophen, diclofenac.Nonsteroidal antiinflammatory drug is more obvious to the side effect of gastrointestinal tract and kidney, and therefore the importance of basic treated with combined medication is appeared suddenly.The wet compound recipe being formed by NSAID (non-steroidal anti-inflammatory drug) diclofenac and misoprostol of omeprazole of U.S. Xi Er large pharmaceutical factory development, treatment of arthritis is evident in efficacy, misoprostol in compound recipe has stronger antiulcer action, but due to expensive, its application can not get popularizing.
Dl-tetrahydr-Opalmatine (dl-tetrahydropalmatine, THP), belongs to the former little Rhizoma Nelumbinis base analogue of tetrahydrochysene (tetrahydroprotoberberines, THPBs).THP divides supination can be divided into levo form (1-THP) and d-isomer (d-THP) through chemistry.Result of study for many years shows, only l-THP has central analgesia, calm, stable effect, and d-THP, without obvious analgesic activity, is emptying dose of the interior dopamine (DA) of brain.L-THP clinical application is called rotundine (rotundine), there is the clinical service time that reaches 40 years, analgesia effect is reliable, and chronic, persistence dull pain are had to good therapeutical effect, and its analgesic activity does not belong to narcoticness analgesia and anti inflammation and heat resolution analgesic category.
Acetaminophen (Acetaminophen is called for short AP) is called and flutters heat breath epilepsy in Britain, is an antipyretic analgesic.First being found in 19 ends, the world, is an active metabolite of the analgesic phenacetin that a kind of toxicity is larger, belongs to phenyl amines.This medicine and nineteen fifty-five are gone on the market by MeNeil laboratory in the U.S., are the best analgesic drug product of market on market at present.The Analgesic Mechanism of acetaminophen is not yet very clear, may be to produce shock effect by suppressing synthetic (comprise and suppress prostaglandin synthetase) of prostaglandin (PG) in central nervous system and the impulsion of blocking-up pain nerve tip, the latter may with material (as 5-hydroxy tryptamine, Kallidin I etc.) synthetic relevant of suppressing prostaglandin or other and can make pain receptor sensitivity.The acetaminophen of low concentration stimulates the generation of PGs, and the generation of PGs always of the acetaminophen of high concentration.Robak in the research of the COX of cattle seminal vesicle microsome enzyme (Prostaglandin Cyclooxygenase) reported first the two-way activity of this medicine.There is arguement in the binding mode of acetaminophen, it is generally acknowledged that at present it is by suppressing Cycloxygenase-3(COX-3 for many years always) work, but also need more research.
At present, aspect treatment of arthritis, there is not yet using tetrahydropalmatine or by tetrahydropalmatine and acetaminophen coupling the medicine as main active.
Summary of the invention
Acetyl aminophenol can be used for treating knee osteoarthritis, but larger poison is secondary uses effect because heavy dose of acetaminophen has, so has limited the application in this respect of this medicine.The inventor finds under study for action unexpectedly, reduces after the dosage of acetyl aminophenol, and it is combined and can obtain good antiphlogistic effects with tetrahydropalmatine.
Based on above research, find, one of object of the present invention is to provide a kind of pharmaceutical composition comprehensive, treatment of arthritis that toxic and side effects is low and cheap that acts on.The tetrahydropalmatine that this medicine contains special ratios and acetaminophen, because two medicine mechanism of action interact, form compositions after antiinflammatory action more comprehensive, and two medicines have share synergism, its antiinflammatory action is obviously better than the folk prescription of same dose.
In order to realize object of the present invention, inventor studies by lot of experiments, has finally obtained following technical scheme:
A pharmaceutical composition for treatment of arthritis, this pharmaceutical composition contains tetrahydropalmatine and acetaminophen.
Preferably, the pharmaceutical composition for the treatment of of arthritis as above, wherein the weight ratio of tetrahydropalmatine and acetaminophen is 1:0.5-4.
Further preferably, the pharmaceutical composition for the treatment of of arthritis as above, wherein the weight ratio of tetrahydropalmatine and acetaminophen is 1:1.5.
Again further preferably, the pharmaceutical composition for the treatment of of arthritis as mentioned above, the raceme that wherein said tetrahydropalmatine is tetrahydropalmatine or levo form.
The pharmaceutical composition for the treatment of of arthritis of the present invention is oral formulations.Preferably, described oral formulations comprises tablet, capsule, granule, oral liquid.Further preferably, the oral formulations described in per unit contains tetrahydropalmatine 20mg, acetaminophen 20-30mg.
By animal experiment study, we find that compositions provided by the present invention can suppress the pedal swelling of model of adjuvant arthritis in rats, effectively regulate PGE in Plasma TNF-α and tissue
2activity.Therefore, two of object of the present invention be to provide a kind of new pharmaceutical composition for the preparation of the purposes in the medicine for the treatment of of arthritis; That is: the compositions that tetrahydropalmatine and acetaminophen form application in the medicine of preparation treatment of arthritis as active component.Preferably, the compositions that rotundin and acetaminophen form application in the medicine of preparation treatment of arthritis as active component.
Compared with prior art, the pharmaceutical composition tool the present invention relates to has the following advantages and is significant progressive:
(1) the most important advantage of the present invention is collaborative antiinflammatory, can effectively regulate PGE in Plasma TNF-α and tissue
2activity, thereby reach the object of curing rheumatoid arthritis;
(2) in the situation of identical curative effect, reduced the consumption that tetrahydropalmatine and acetaminophen are used separately, especially significantly reduced the consumption of acetaminophen, thereby the expense of patient's medication is reduced, reduce the toxic and side effects of acetyl aminophenol simultaneously, increased the safety of medication and patient's compliance.
The specific embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is done to further description, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
Embodiment 1 experimental animal model of CFA induced adjuvant arthritis in rats experiment
40 of SD rats, body weight 180-220g, conventional adaptation was raised after one week, set up the pathological model of adjuvant-induced arthritis in the sufficient sole of the foot intradermal injection Freund's complete adjuvant 0.1mL of portion of rat right hind leg.The successful adjuvant arthritis rats of modeling is divided into four groups at random by body weight, be totally 4 groups of model control group, rotundin group (20mg/kg/d), acetaminophen group (30mg/kg), compositions group (rotundin 20mg/kg/d+acetaminophen 30mg/kg/d), 10 every group.After modeling the 4th day, rotundin group, acetaminophen group, compositions group rat are carried out to the medicine that gavage gives corresponding dosage, the isopyknic purified water of model control group gavage, each organizes every day 1 time, and administration is three weeks altogether.
Rat respectively at modeling before, the variation of measuring the sufficient sole of the foot Zhou Jing of right hind fixed position with fine rule and ruler before administration, after administration three weeks.After last administration 5 hours, sterile working under etherization, from heart blood drawing 2-3 mL, anticoagulant heparin, isolates blood plasma, is placed in-20 ℃ and preserves Plasma TNF-alpha actives to be measured.On the left back ankle joint of every rat, 0.5cm place cuts inflammatory swelling foot, weigh, peeling, shreds, normal saline 5rnl soaks 1 hour, take out Mus pawl, centrifugal soak, draws supernatant 0.1rnl, the KOH-methanol solution 2ml that adds 0.5mol/L, in 50 ℃ of water-baths, isomerization is 20 minutes, with methanol, is diluted to 20ml, in wavelength, is that 278nm place measures its optical density value (OD).With every gram, organize suitable absorbing light density value to represent PGE
2activity, as evaluating antiinflammatory index.
Result of the test by table 1 can be found out, there is height swelling in each modeling rat the 3rd day right back ankle joint after modeling, after administration three weeks, rotundin or acetyl aminophenol suppress effect on pedal swelling a little less than, and after drug combination, the two obtains significant synergism on reduction model of adjuvant arthritis in rats pedal swelling.
The comparison of right hind foot sole of the foot Zhou Jing before and after table 1 administration
With comparison before modeling,
* p< 0.01; Before and after administration, self compares,
# p< 0.05,
## p< 0.01; With model group comparison,
△ p< 0.05,
△ △ p< 0.01; With the comparison of tetrahydropalmatine group,
★ ★ p< 0.01; With the comparison of acetaminophen group,
● ● p< 0.01.
Result of the test by table 2 can find out, rotundin has the activity of certain reduction model of adjuvant arthritis in rats TNF-α, but to PGE
2not effect; Acetaminophen is to PGE
2there is certain reducing effect, but on not impact of TNF-α.Compositions group after two medicine couplings, it is at reduction TNF-α with from PGE
2in two indexs, all obtained good concertedness effect.
Table 2 is respectively organized PGE in Plasma TNF-α and tissue
2result comparison
With model control group comparison
* p< 0.05,
* p< 0.01;
With the comparison of tetrahydropalmatine group,
# p< 0.05,
## p< 0.01;
With the comparison of acetaminophen group,
△ p< 0.05,
△ △ p< 0.01.
Claims (9)
1. a pharmaceutical composition for treatment of arthritis, is characterized in that: described pharmaceutical composition contains tetrahydropalmatine and acetaminophen.
2. the pharmaceutical composition for the treatment of of arthritis according to claim 1, is characterized in that: the weight ratio of tetrahydropalmatine and acetaminophen is 1:0.5-4.
3. the pharmaceutical composition for the treatment of of arthritis according to claim 2, is characterized in that: the weight ratio of tetrahydropalmatine and acetaminophen is 1:1.5.
4. according to the pharmaceutical composition for the treatment of of arthritis described in claim 1-3 any one, it is characterized in that: the raceme that described tetrahydropalmatine is tetrahydropalmatine or levo form.
5. according to the pharmaceutical composition for the treatment of of arthritis described in claim 1-3 any one, it is characterized in that: described pharmaceutical composition is oral formulations.
6. the pharmaceutical composition for the treatment of of arthritis according to claim 5, is characterized in that: described oral formulations comprises tablet, capsule, granule, oral liquid.
7. the pharmaceutical composition for the treatment of of arthritis according to claim 5, is characterized in that: the oral formulations described in per unit contains tetrahydropalmatine 20mg acetaminophen 20-30mg.
8. the compositions that tetrahydropalmatine and acetaminophen form application in the medicine of preparation treatment of arthritis as active component.
9. the compositions that rotundin and acetaminophen form application in the medicine of preparation treatment of arthritis as active component.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410173902.5A CN103919776B (en) | 2014-04-29 | 2014-04-29 | A kind of pharmaceutical composition for the treatment of of arthritis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410173902.5A CN103919776B (en) | 2014-04-29 | 2014-04-29 | A kind of pharmaceutical composition for the treatment of of arthritis |
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| CN103919776B CN103919776B (en) | 2016-03-02 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351308A (en) * | 2006-09-03 | 2013-10-16 | 于崇曦 | Positively charged water-soluble 4-acetamidophenol having rapid skin penetration speed, and related compound prodrug thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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