Application of sinomenine in rheumatic diseases

Hai-Yu Wang,Chen-Hui Song,Xiao-Ping Liu,Tang-Liang Qian,Yue-Lan Zhu,Xiu-Juan Hou

1Beijing University of Chinese Medicine,Beijing,China.2Dongfang Hospital,Beijing University of Chinese Medicine,Beijing,China.

Abstract Sinomenine is widely used in a variety of rheumatic diseases,and more and more attention has been paid to the adverse reaction in allergic reactions,digestive tract,blood,circulatory and nervous system.The application of sinomenine in rheumatoid diseases and its side effects were reviewed here,which may provide a reference for the safe and effective application of sinomenine preparations.

Key words:Sinomenine,Rheumatic diseases,Clinical application,Side effects

Introduction

Sinomenine(SIN)is an active ingredient extracted from Qingfeng vine.The molecular formula is C19H23NO4 with a 329.38 relative molecular mass.The current medicine dosage forms includes the injection,enteric-coated tablets and sustained-release tablets.Because the effects of anti-inflammatory,immunosuppressive, analgesic, anti-hypertensive,anti-arrhythmic and other pharmacological effects[1],it is widely used in clinical treatment of a variety of rheumatic diseases,including rheumatoid arthritis(RA),osteoarthritis(OA),spondylitis,systemic lupus erythematosus,gout,etc,with rapid onset and long-term efficacy.However,the adverse reactions such as allergy and adverse reactions of digestive system and hematological system have gets wide attention[2].The safe and effective application of sinomenine in clinical is current focus.Here,we have reviewed the recent researches,and make a summary for the application and adverse reactions of sinomenine in rheumatic diseases,to provide a reference for the future more reasonable application.

Mechanism of SIN in rheumatic diseases

The mechanism of SIN in rheumatoid arthriti

The anti-inflammatory and analgesic effects of SIN.The main pathogenesis of RA is synovial inflammation.Zhou et al[3]applyed SIN combined with methotrexate(MTX)for 60 patients with RA and found that the level of TNF-α after treatment significantly decreased.It is suggested that SIN may reduce the inflammatory reaction by inhibiting the expression of TNF-α and other inflammatory factors in the synovium of RA patients.TLRs are involved in developmentand progression ofRA.Myeloid differentiation factor 88 is an important adapter protein with TLR structural domain.The activation of TLR4 are involved in the inflammatory response of RA by initiating inflammatory responses and releasing inflammatory cytokines which activate NF-κB through the MyD88-dependent pathway[5].Mu et al[6]found that the expression of MyD88 protein and mRNA increased in the synovial tissue of adjuvant arthritis(AIA)rats model,and SIN could significantly reduce the MyD88 expression in synovialtissue ofAIA rats and controlthe inflammatory response, suggesting that SIN treatment of RA may be related to MyD88-mediated inflammatory pathways.

Fibroblast-like synoviocytes(FLS)is the most important cell in RA synovial membrane and plays an important role in the pathogenesis of RA[7].Chen et al[8]found that SIN can significantly inhibit the expression of vascular cell adhesion molecule induced by TNF-α and the release of inflammatory factors and chemokines of IL-6,CCL2 and CXCL8(p＜0.05).SIN could regulate the levels of IFN-γ and IL-4 in peripheral blood of patients with RA,induce the production of anti-inflammatory cytokine IL-4 and inhibit the expression of IFN-γ,which play a role in controlling the disease[9].Ali AM[10]found that Nitric oxide(NO)was significantly associated with RA disease activity,inflammatory markers and sharp score.Arginine and citrulline are two importantamino acids involved in NO metabolism.Shao et al[11]measured the levels of two amino acids in rabbits synovial fluid after SIN intragastric in vivo microdialysis experiments,confirmed the inhibitory effects of SIN on arginine and citrulline in synovial fluid,but also suggested inhibitory effect of SIN on NO.

The Immunosuppressive effects.RA is a chronic long-term autoimmune disease.Lietal[12]researched the mechanism of SIN on T helper T cells 17/regulatory T lymphocytes cells ratio from the cellular level,the results suggested that the drug plays a role in the treatment of RA through inhibiting increase of Th17.Osteoclasts play a key role in the pathogenesis of RA[13].Receptor activator for NF-κB Ligand(RANKL),a member of the TNF-α superfamily,can induce osteoclastic proliferation and differentiation of cell precursors,and promote the expression of a series of osteoclast genes by binding to the RANKL receptors of osteoclast precursors.Osteoprotegerin(OPG)produced by osteoblasts and stromal cells can block the binding of RANKL to RANKL receptors.The ratio of RANKL to OPG plays an important role in controlling osteoclast differentiation and bone resorption[14,15].Sun et al[16]investigated the regulatory mechanism of SIN combined with MTX on osteoclast-associated cytokines in RA rats model.Serum levels of RANKL,OPG,IL-6,IL-17 and matrix metalloproteinases weremastered by ELISA,Theexpression of cytokines related to FLS osteoclasts in RA patients was detected by RT-PCR.The results showed that the combination of the two could significantly inhibit the production of synovial RANKL and OPG.And the combination has a synergistic effect on the down-regulation of RANKL,IL-6,IL-17 and MMPs in the serum of rats,alleviating the inflammatory reaction and joint damage in rats consequently.Some studies[17]found that cyclic citrullinated peptide(CCP)is involved in the pathogenesis of RA as an early pathogenic target antigen of RA.Chou et al[18]observed the impact of SIN on CCP antigen-specific T cells proliferation in vitro and found that CCP could induce peripheral blood lymphocyte proliferation in RA patients in vitro(P＜0.01).On the basis of this,the proliferation effectof lymphocytes induced by CCP was significantly inhibited(P＜0.01),and the inhibition of SIN high-dose group was more significant than that of the low-dose group(P＜0.01),suggested that SIN could inhibit the activation and proliferation of CCP-AST in RApatients in vitro.

The inhibition in proliferation of synovial cell.The most remarkable tissue change in the pathological mechanism ofRA is synovialtissue,which infliltrated by a large number of macrophages,lymphocytes and neutrophils from pathological synovial fluid,and caused bone and cartilage damage through the interaction with inherent synovial cells[19].FLS is a major cell in synovial cells involved in the pathogenesis of RA.Sun et al[20]studied the effectofSIN combined with MTX on the proliferation and apoptosis of FLS cultured in vitro in RA patients.TheOD valueofRA-FLS proliferation in each experimental group was lower than that of the control group.This indicates that SIN combined with MTX can inhibit FLS synergistically.This may be one of the mechanisms that reduce RA bone damage.Zhang et al[21]studied the effect of expression that SIN on MyD88 in RA-FLS and Tumor necrosis factor receptor associated factor-6(TRAF-6).The expression of MyD88 and TRAF-6 in control group and 0.5 mmol/L SIN group were detected by real-time fluorescence quantitative PCR.The expression of MyD88 and TRAF-6 protein in the two groups were measured by Western blot.The results showed thatthe mRNA and protein expressions of MyD88 and TRAF-6 in 0.5 mmol/L SIN group were lower than those in control group(P＜0.05),suggested that the effect of SIN on TLR signal transduction pathway inhibited the expression of MyD88 and TRAF-6 in RA-FLS cells,therefore prevented the destruction of cartilage and subchondral bone in RA patients and slowed the progression of the disease.Ou et al[22]found that SIN significantly inhibited the migration and invasion of FLS in vitro co-cultured with activated human monocytic THP-1 cells in a concentration-dependent manner,and it may related to inhibit the expression of CD147,MMP-2,MMP-9.

The mechanism of SIN in osteoarthritis

Osteoarthritis(OA)isa chronic jointdisease characterized by progressive loss of articular cartilage and hyperosteogeny.The clinical symptoms include chronic joint pain,stiffness,hypertrophy and limited mobility.MMP-13 can strongly degrade the cartilage matrix and play an important role in the pathogenesis of OA[23].Cartilage oligomeric matrix protein (COMP)are highly expressed in the cartilage,which mainly expressed in cartilage and synovial cells[24].The level of serum COMP can predict the extent of OA lesions[25].Zheng et al[26]studied the effects of SIN on MMP13 and COMP in serum and synovial fluid in rabbits model.The results showed that the levels of MMP-13 in serum and synovial fluid of SIN group were significantly lower than that of model group,while the level of COMP in synovial fluid decreased(P＜0.05,P＜0.01),suggested that SIN may improve the synovial inflammation of OA through this pathway,and slowed the progression of articular cartilage degeneration.Zhu et al[27]divided 86 OA patients into experimental group and control group.The experimental group was treated with Zhengfengfengtongning Tablet(the main component of SIN hydrochloride),the controlgroup with glucosamine-hydrochloride. The levels of interleukin-1β (IL-1β)and TNF-α in serum were detected after 12 weeks of treatment.The results showed that Zhengfengfengtongning Tablet could effectively relieve the clinical symptoms of OA patients and significantly inhibit the level of IL-1β and TNF-α in serum.It is an effective therapy for OA.The proliferation of osteoclasts in the OA early stage indicated that osteoclasts may be involved in the formation of OA[28].Zhou et al[29]found that SIN inhibited osteoclast differentiation by inhibiting the ratio of OPG/RANKL induced by PGE2.The results showed thatSIN could inhibitthe excessive activation of osteoclasts.Ju et al[30]studied the protective effects of SIN on IL-1β-induced proteoglycan degradation and apoptosis in rabbit articular cartilage and chondrocytes,and found that SIN could antagonize cartilage degeneration and chondrocyte apoptosis.

The mechanism of SIN in ankylosing spondylitis

Ankylosing spondylitis(AS)isa chronicand progressive disease that primarily affects sacroiliac joints,spine,and peripheral joints[31].SIN can be an effective treatment for AS with low adverse reaction rate[32].Huang et al[33]investigated the proteomic changes in peripheral blood mononuclear cells from 30 patients with AS.Eight differentially expressed proteins were found in SIN-treated PBMCs,of which seven were up-regulated,including α-synuclein,calmodulin,family member A of the acidic leucine-rich nucleophosmin 32,intracellular chloride,gelsolin and histone H2B 1-M of guanine nucleotide binding protein G(I)/G(S)/G(T)β-1. While the downregulated expression of canonin may be part of the mechanism for the effects of SIN on AS.TNF-α is a class of non-species-specific cytokines with multiple biologicalactivities.Asafactorthatmediates inflammation and immune regulation it plays an important role in the pathogenesis of AS and can be regarded as an important marker to evaluate the severity of AS [34].The studies[35]divided peripheral blood mononuclear cell from normal persons into five groups and treated with 0.9%sodium chloride injection,high,medium and low doses of SIN and dexamethasone,respectively.They obeserved that the level of TNF-α in high-dose SIN group was significantly lower than that in mediumand low-dose groups(P＜0.05),and the mRNA level of TNF-α in PBMC was lower than 0.9%Sodium injection group significantly.Inhibition of expression of TNF-α in human peripheral blood mononuclear cell may be one of the mechanisms of SIN for the treatment ofAS.

The mechanism of application that SIN in other rheumatic diseases

Growth differentiation factor 2(GDF2)can induce osteogenic differentiation and bone formation[36].Huang et al[37]studied the effects of SIN on the expression of GDF2,IL-1β and IL-17 in serum in rat model with osteoporosis compressibility fracture,they found that SIN could improve inflammatory reaction and bone degeneration mediated by IL-1β/IL-17,improve the ability of GDF2 to induce osteogenic differentiation and bone formation and accelerate the healing of fractures.Some studies[38]found that SIN could inhibit the production of IFN-C,IL-2 and IL-4 by peripheral blood T cells in patients with systemic lupuserythematosus,and could significantly reduce the expression of CD69 and CD25 on CD4+T and CD8+T cells.It is demonstrated that SIN could exert immunosuppressive effects by inhibiting the activation of T cells and the secretion of cytokines.Yin et al[39]demonstrated that SIN had an anti-inflammatory effect on gouty arthritis through effectively reducing the levels of TNF-α,IL-1β and COX-2 and inhibiting themalignantcycleof inflammatory cytokines in rat model.Meanwhile,local injection method could quickly play a role in reliving joint pain.

The side effects of SIN

SIN can cause allergic reactions

A meta-analysis of the adverse reactions caused by Zheng feng feng tong ning showed that pruritus was the main clinical adverse reaction,with an incidence of 8%[40].Tang et al[41]reported a patients with no history of allergicnephroticsyndrome,the apperance of systemic skin irritation after using SIN sustained-release tablets,which was prominent diffuse rash in the dermis with visible scratches and dander.It was consider drug-induced exfoliative dermatitis.Song et al[42]reported that one patient with RA had been given oral aspirin orally combined with Zhengfengfengtongning Tablet 60 mg,severe allergic reactions on ear,nose and throat were found after 10 minutes.A study reported 32 cases of drug eruption caused by Zhengfengfengtongning Tablet,including 10 males and 22 females,28 cases of drug eruptions in the exposed areas of the face,neck,ears and hands,the initial issuance of two legs,buttocks and other non-exposed parts for other 4 cases,patients are accompanied by drama itch.Drug eruption forms include measles-like, scarlet fever-like,erythema multiforme-like,urticaria-like.SIN is strong histamine release agent for its strong histamine release,and its role of promoting histamine release is related to skin allergies and drug eruption.Therefore,in order to prevent adverse reactionscaused by SIN,some scholars[44]suggested taking the drug from a small dose.Allergic constitution should be used with caution or disabled,Avoid eating high fat,high protein diet when taking SIN.In case of itching and other adverse reactions,it should be dealt with immediately.

SIN on the digestive system adverse reactions

Adverse reactions of digestive system caused by SIN mainly including nausea and vomiting,loss of appetite,dry mouth,bloating and so on.In addition,Wu et al[45]found that Zhengfengfengtongning Tabletcould cause drug-induced liverdamage through conducting clinical trials which treatment of idiopathic focal segmental glomerulosclerosis.Thus,before taking medication,much attention to the patient'spasthistory,family history and other conditions should be paid,and liver function should be regularly monitored.SIN has a short biological half-life[46],it is necessary to use appropriate dosage forms to change the irritation and instability of SIN raw materials on account of the long treatment cycle and gastrointestinal side effects induced by large dose.Some scholars [47]summarized the clinical trials of SIN modified formulations showed that gel,cream,spray,patch and other transdermal drug delivery is convenience and could provide a longer time without the first pass through the liver,maintain the level of treatment of plasmaconcentration,reduce drug toxicity and adverse reactions to the gastrointestinal tract,to achieve the purpose ofreducing toxicity and increasing efficiency.However,transdermal delivery of SIN still remain in the stage of experimental research,and has not been reported in clinical application,so further study is needed.

SIN on the blood,circulation and nervous system damage

Chen et al[48]reported agranulocytosis in 44 patients with systemic lupus erythematosus and systemic sclerosis after SIN treatment.The adverse reaction was treated using granulocyte-colony stimulating factor and antibiotics after stopping the SIN.The number of granulocytes returned to normal after 10 days.It suggests that it is necessary to closely monitor bone marrow function and granulocyte numbers during treatment with SIN.Li et al[49]found that the drug can cause heart palpitations,dizziness,redness,hypotension and other symptoms through the analysis of Zhengfengfengtongning Tabletinjection adverse reactions.The reason of above symptoms may be the release of histamine caused by SIN,which leading to sympathetic nerve stimulation.Meanwhile histamine can reduce blood pressure as a vasodilator that can lead to peripheral vasodilation.

Conclusion

TCM hasalonghistory inthetreatmentof rheumatism.In recent years,the more popular study of Grifola frondosa and its SIN hydrochloride fully embodies the essence of TCM theory.The research on SIN has progressed from the clinical efficacy to the immune mechanism.However,for now,there are relatively more studies on the mechanism of SIN on RA,but fewer studies have been done on other rheumatic diseases.Therefore,in-depth study of its role in the treatment of rheumatoid diseases and its mechanism,the fullintegration and scientific analysis of pharmacokinetic data and adverse reactions to maximize the efficacy while avoiding the side effects is the direction that we need to work hard.