CN1843339A - Use of resveratrol in treating rheumatoid arthritis and non-inflammatory disease - Google Patents
Use of resveratrol in treating rheumatoid arthritis and non-inflammatory disease Download PDFInfo
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- CN1843339A CN1843339A CN 200510031435 CN200510031435A CN1843339A CN 1843339 A CN1843339 A CN 1843339A CN 200510031435 CN200510031435 CN 200510031435 CN 200510031435 A CN200510031435 A CN 200510031435A CN 1843339 A CN1843339 A CN 1843339A
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Abstract
The invention relates to an application of resveratrol in drug treating atrophic arthritis and non-infectious inflammation. The usage method is that: oral 20 mg/kg, three months as a course of treatment and for 2-3 curses; and 10mg/kg, one month as a course of treatment and for 1-2 courses. The effect is better than leflunomide, ledertrexate, and pavlin when resveratrol is used to treat atrophic arthritis; and the effect is better than acetophen when it is used to treat non-infectious inflammation.
Description
Technical field
The present invention relates to the application of a kind of resveratrol in Drug therapy rheumatoid arthritis, non-infectious inflammation.
Background technology
Resveratrol claims Rhizoma Polygoni Cuspidati extract again, and name of commodity in English is Polygonum Cuspldatum P.ETrans-resveratrol, and the chinesization formal name used at school is 3,5,4 '-trihydroxy stilbene, English chemistry by name 3,5,4 '-trihydroxy-trans-stilbene, molecular formula C
14H
12O
3, molecular weight 228.2, structural formula is
The pharmacological action of resveratrol briefly is summarized as follows:
1, suppresses cell DNA and synthesize, suppress cell proliferation
The synthetic of DNA is the essential condition of cell division propagation, and with RNA reductase activity, dna polymerase activity, and DNA production concentration self feed back mechanism is relevant.Studies show that resveratrol suppresses the activity of RNA reductase by the tyrosyl-of removing small protein DNA reductase; suppress archaeal dna polymerase; with the activation of inducing cysteine proteinase caspase-3 and decomposing D NA repairase modes such as (poly-A polymerases) suppresses the synthetic of DNA, thereby suppress cell proliferation.
2, suppress the oxidative stress transcription factor, suppress cell proliferation
The nuclear factor (Ap-1) of nuclear factor-k β (NF-KB), early gene coding is called as the oxidative stress transcription factor, participates in the regulation and control of cell cycle.The propagation of its state of activation and cell is closely related.Active oxygen promotes the cell growth as the second message,second messenger of cell to the somatomedin reaction.Resveratrol is ultra-oxygen anion free radical and the very strong trapping agent of hydroxy radical, and it can improve the content of glutathion simultaneously, suppresses cell activity oxygen, influences the cellular oxidation reducing condition, suppresses cell proliferation.
3, cell death inducing, the propagation of control cell
Apoptosis is a kind of mode that tissue upgrades.If apoptosis reduces, pathologic propagation will appear, cause disease.Resveratrol can be reduced the gene expression of Bcl-2 and raise Bax gene expression; Activate mapk kinase, P38 kinases, increase the endogenous ceramide, induce the Fas receptor expression and suppress mitochondrial respiratory chain and induce mitochondrial permeability to change the opening of passage and cell death inducing, the control cell proliferation.
4, inducing cell Cycle Arrest, the control cell proliferation
Plain dependent kinase (CDK) of resveratrol cycle capable of inhibiting cell, transcribing of p21WAF1/C1P1 induced in the retardance of inducing cell cycle S～G2, makes the retardance of cell cycle G1～S, from two link control cell proliferation.
5, suppress COX-2 (COX-2), have analgesic and anti-inflammatory effects
COX-2 can induce arachidonic acid to be converted into prostaglandin, participates in inflammatory reaction, and the nocuity receptor is improved the sensitivity of morbid substance.This is that non-infective inflammation is red, swollen, hot, the root of pain.Resveratrol suppresses COX-2 gene expression by Profilin kinase c (PKC) signal transduction pathway and brings into play analgesic and anti-inflammatory effects.
6, free radical resisting damage, it is synthetic to suppress platelet aggregation and 20 alkane, reduces lipid peroxide, and microcirculation improvement is prevented and treated tissue ischemia anoxia-reperfusion injury significantly.
Resveratrol still belongs to a kind of new drug just under study for action abroad, is used for the chemoprophylaxis treatment of cancerous protuberance, dosage 3～8mg/kg; At home, resveratrol is as the health product exploitation with the cardiovascular disease of preventing and treating, as " day lion vigor capsule ", " the Zijin capsule ", " receive shellfish benefit rubber capsule " etc.
Summary of the invention
The purpose of this invention is to provide the using method of a kind of resveratrol in Drug therapy rheumatoid arthritis, non-infectious inflammation, for rheumatoid arthritis, non-infectious inflammatory patients provide a kind of new medicine.
The application of resveratrol in the Drug therapy rheumatoid arthritis, its using method is: 20mg/kg is oral, 3 months one courses of treatment, 2～3 courses of treatment of logotype.
The application of resveratrol in non-infectious inflammation, its using method is: 10mg/kg is oral, 1 month one course of treatment, 1～2 course of treatment of logotype.
Adopt resveratrol to modify antirheumatic treatment rheumatoid arthritis, be better than leflunomide, methotrexate, Pa Fulin as pathological changes.
Rheumatoid arthritis is a kind of autoimmune disease based on the chronic progressive external arthropathy, it is characterized in that the symmetry polyarthritis, it is the most common to get involved with both hands, wrist, elbow, knee joint, ankle and joints of foot, but other joints of whole body also can get involved, what have also gets involved with internal organs.Can delay repeatedly for many years without correct treatment, finally cause joint deformity and afunction.The title that carcinoid is arranged.Be one of 16 kinds of definite refractory diseases of national medical insurance.Primary disease is more common, and sickness rate is about 0.26%～0.5%.Any age per capita can be ill, onset peak was at 40～50 years old.Its pathogenesis is not illustrated so far as yet, thereby does not just have special effect medicine therapeutic yet.Present Therapeutic Principle modifies the progress of antirheumatic with the control arthropathy with acting on antirheumatic or pathological changes slowly, with NSAID (non-steroidal anti-inflammatory drug) alleviate swollen, bitterly, symptom such as deadlock and improve its movable function.The pathological changes of present clinical use is modified antirheumatic methotrexate, sulfasalazine, oxychloroquine, auranofin, penicillamine, leflunomide, ring phosphinylidyne ammonia, ciclosporin A, 99 technetiums-methylene phosphate etc.The shortcoming of these medicines is that untoward reaction is heavy and many, as serious gastrointestinal reaction, and hepatic and renal function injure, leukocyte, thrombocytopenia etc.; The shortcoming of NSAID (non-steroidal anti-inflammatory drug) is that symptom is easily bounced after the drug withdrawal, can not stop the arthropathy progress, untoward reaction is also heavy and many, as serious gastrointestinal reaction, gastrointestinal hemorrhage, perforation, and the heart, blood vessel, liver, nephrotoxicity etc., medicines such as rofecoxib, Phenylbutazone are owing to the untoward reaction of this respect is seriously quit listing.Have in view of that, the various countries scholar is seeking and is developing high-efficiency low-toxicity technetium medicine energetically.Entering the I phase abroad in 2003, clinical medicine of II phase has: the cox 2 inhibitor of pharmacia company, penta ground former times cloth (valdecoxib); The NF-kB of Toyama company activates inhibition-iguratimod (T-614); Preparation-the paclitaxel (paclitaxel) of the blocks protein complex activator protein (AP-1) of Angiotech company; Metalloproteases (MMP) the inhibitor recombination human interleukin-10 (ilodecakin) of the Ling of elder generation-Pu Fen company etc. 22.
Modern study is thought, the pathogenesis of RA may be the structure homology that there are one section common sequences QK/RRAA and antibacterial or virus in patient's interior glycoprotein, II collagen type and the A type synovial cell surface of articular cartilage, causes the pathologic autoimmune response after by this antibacterial or viral infection; Or because by due to the pathologic autoimmune response of the mediation of the fuzzy diagnosis between TXi Baoshouti and the human leucocyte antigen (HLA).Its pathological characteristic is that synovium of joint hypertrophy, inflammatory cell infiltration and pannus form, and then formation " pannus-cartilage land ", the local host metalloproteases increases, proteoglycan reduces and cytokine secretion increases, cause cartilage destruction and then formation " pannus-bone complex zone ", cause the erosion and the destruction of bone, cause joint fusion, damage, afunction.So-called " pannus " be a kind of be the granuloma tissue of feature with blood vessel hyperplasia and inflammatory cell infiltration.Someone likens it to class tumor sample pathological changes.Pathological section shows that the synovial cell thickens and reaches 3～7 layers, and a large amount of CD+4 cells, B cell, plasma cell, macrophages infiltration are arranged around the blood vessel.Immunohistochemical study prompting, IL-1, IL-6, IL-8, TNF-α, TGF-β, GM-CSF, M-CSF, MCP-1, MMP increasing expression in the joint tissue, anti-apoptotic proteins Bcl-2 expresses enhancing, and the apoptosis effect weakens etc.In addition, inflammatory cytokine, immune complex, complement, kassinin kinin and neuropeptide, protease, nitric oxide and oxygen-derived free radicals etc. all play an important role in the pathological lesion of RA.Molecular biosciences studies show that the DNA of inflammatory cell is synthetic to be increased, and it is the core of RA molecular pathology that the oxidative stress transcription factor is activated.
According to the pathogenesis of RA, the inhibition cell DNA of resveratrol synthesizes, suppresses oxidative stress transcription factor, cell death inducing, brings out the pharmacological action of cell cycle arrest, has and utilizes the propagation that suppresses or control cell, blocks the formation of pannus.The mechanism of action of improving methotrexate (MTX) in the state of an illness antirheumatic, leflunomide (LEF) with the Drug therapy RA that generally acknowledges now is similar.MTX, LEF can not only effectively improve the state of an illness, and can stop or repair the infringement of B﹠J.The inhibition COX-2 of resveratrol and antioxidant radical damage, it is synthetic to suppress platelet aggregation and 20 alkane, reduce lipid peroxide, microcirculation improvement significantly, control tissue ischemia, anoxia-reperfusion injury ground pharmacological action, to improve the mechanism of action of Chinese herbal medicine of symptom ground NSAID (non-steroidal anti-inflammatory drug) (as celecoxib, meloxicam, diclofenac, nabumetone, loxoprofen etc.) and activating blood circulation to dissipate blood stasis similar with being used for the treatment of RA now.In sum, the effect of many target position of resveratrol has the pharmacological action for the treatment of both the principal and secondary aspects of a disease to RA.
Resveratrol is treated non-infectious inflammation as nonsteroidal anti-inflammatory drug, is better than NSAID (non-steroidal anti-inflammatory drug) such as aspirin.
Non-infectious inflammation comprises the inflammation of osteoarthrosis due to the various rheumatism and surrounding tissue thereof, and tissue is wounded, sprained, surgical injury, toothache, dysmenorrhea etc.In other words, non-infectious inflammation is meant that various chemistry, machinery or thermostimulation can activate the nociceptor of periphery, causes and organizes congestion and edema, pain etc.For example the P material directly by the medullated A fiber and the release of unmyelinated C nerve fiber of infringement, directly or indirectly makes mast cell degranulation, causes vasodilation or forms edema.Thereby P substance activating phospholipase A2 produces arachidonic acid, is converted into prostaglandin (PG) by cyclooxygenase (COX) again.PG can make nociceptor that the sensitivity of algogenic substance (histamine, Kallidin I, 5-hydroxy tryptamine, P material) is improved, and causes pain.PG can cause part and systemic inflammatorome (leukoplania is organized congested, edema, causes inflammation for vasodilation, permeability increase) again on the other hand, even heating.
Extracting salicylic acid before more than 100 years from bark of willow has had since the analgesic and anti-inflammatory effects, now existing tens of kinds of structures are incomplete same, but the nonsteroidal anti-inflammatory drug of its function all similar, its mechanism of action all is to suppress COX, and just the inhibition degree to two isozymes (COX-1 and COX-2) of this enzyme has difference.This class medicine is all more common to the untoward reaction of gastrointestinal, kidney, blood system, central nervous system, liver function etc., in the last few years American-European countries to have gone on the market again with celecoxib, rofecoxib be the novel antalgic anti-inflammatory agent of representative.Though they have reduced the gastrointestinal serious adverse reaction, and the untoward reaction of cardiovascular, kidney is increased along with increasing of clinical use.Last October, rofecoxib (ten thousand networks) is announced to stop using in the whole world, the seriousness of visible problem.
Safety is good, has no adverse reaction.Resveratrol is a kind of bouvardin, or is plant complement (phytoalexin).In 72 kind of plant such as Rhizoma Polygoni Cuspidati, Pericarpium Vitis viniferae, Semen arachidis hypogaeae, Sangzhi, can extract acquisition.Use 18 weeks of 25umol (5.7mg/kg), do not show any untoward reaction.Bhat studies show that and 120 days, not observe untoward reaction to mouse feeding resveratrol 300mg/kg.
The specific embodiment
Embodiment 1, be used for the treatment of rheumatoid arthritis
The inductive rat arthritis animal model of II Collagen Type VI is the classics experiment of research Drug therapy RA.80 Waist rats are divided into normally at random, model, medicine (8mg/kg, 16mg/kg, 32mg/kg) 3 dosage and positive drug (leflunomide 0.4mg/kg/d, methotrexate 0.3mg/kg/w, Pa Fulin 30mg/kg/d) 8 groups of contrast experimentize, the rat suitability fed for 2 weeks before the experiment, inject 3.5% chloral hydrate (10ml/kg) anesthesia subsequently in the abdominal cavity, every rat divides 8～10 some intradermal injections to contain the Freund's complete adjuvant 1ml of solubility II collagen type (c-1188) 0.5mg, and the 2nd injection of 1 week back row contains the incomplete Freund 1ml of same collagen dosage.Cause scorching d10 later on and begin to change medicine, continuous 28 days.Put to death animal then, carry out sufficient pawl volume determination, tardy allergy detection, the antibody test of anti-II Collagen Type VI, metapedes ankle joint pathology detection, the result shows: the rat that the resveratrol of the above dosage of 16mg/kg is handled can not only suppress anti-II Collagen Type VI production of antibodies and suppress the delayed allergy inflammation, and can significantly improve the joint pathology infringement, better than leflunomide, methotrexate, Pa Fulin treatment effect, prove that resveratrol has the good curing effect to RA.
Embodiment 2, be used for the treatment of non-infectious inflammation
Resveratrol all proves from theory and practice can suppress COX, particularly suppresses COX-2, has analgesic and anti-inflammatory effects.Its intensity is weaker than indomethacin slightly greater than aspirin.Its antioxidation, anti-platelet aggregation effect have protective effect for the cardiovascular hepatic and renal function.Be expected resveratrol can be better than existing nonsteroidal antiinflammatory drug as the medicine for the treatment of non-infectious inflammation.
Claims (2)
1. the application of resveratrol in the Drug therapy rheumatoid arthritis is characterized in that: using method is: 20mg/kg is oral, 3 months one courses of treatment, 2～3 courses of treatment of logotype.
2. the application of resveratrol in non-infectious inflammation is characterized in that: using method is: 10mg/kg is oral, 1 month one course of treatment, 1～2 course of treatment of logotype.
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| WO2019099531A1 (en) * | 2017-11-15 | 2019-05-23 | The Regents Of The University Of Colorado, A Body Corporate | Compositions for improving physiological function with age |
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| WO2019099531A1 (en) * | 2017-11-15 | 2019-05-23 | The Regents Of The University Of Colorado, A Body Corporate | Compositions for improving physiological function with age |
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