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1 Journal of Korean Medicine Rehabilitation Vol. 25 No. 4, October 2015 pissn eissn Review Article ChondroT 구성약물의골관절염관련국내연구동향 - 한의학학술지를중심으로 배길준 정지원 송민영 김태광 김선종동신대학교한의과대학한방재활의학과교실 The Domestic Trends of Osteoarthritis-related Research on Each Constituent Herb of ChondroT - Focused on the Journal of Korean Medicine Kil-Joon Bae, K.M.D., Ji-Won Jeong, K.M.D., Min-Yeong Song, K.M.D., Tae-Gwang Kim, K.M.D., Seon-Jong Kim, K.M.D. Department of Korean Medicine Rehabilitation, College of Korean Medicine, Dongshin University 본연구는보건복지부한의약선도기술사업의지원에의하여이루어진것임 ( 과제고유번호 : HI13C2285). RECEIVED September 30, 2015 ACCEPTED October 10, 2015 CORRESPONDING TO Seon-Jong Kim, Department of Korean Medicine Rehabilitation, Mokpo Oriental Hospital of Dongshin University, 313 Baengnyeon-daero, Mokpo 58665, Korea TEL (061) FAX (061) mofoster@hanmail.net Objectives The purpose of this study is to analyze the osteoarthritis-related effect of each constituent herb of ChondroT, the herbal medicine that used for osteoarthritis. Methods We searched osteoarthritis-related studies on each constituent herb of ChondroT via five Korean Medicine web databases. We classified these studies by each constituent herb (Ostericii Radix, Angelica Gigas Nakai, Clematidis Radix, Lonicerae Flos, Phellodendri Cortex) and researched the osteoarthritis-related effect. Results We collected 18 studies (two studies of Ostericii Radix, five studies of Angelica Gigas Nakai, three studies of Clematidis Radix, six studies of Lonicerae Flos, and two studies of Phellodendri Cortex). All of these studies were composed of in vivo and in vitro, and there were six pharmacopuncture experimental study. All experiments showed the significant effects on specific inflammatory mediators. Conclusions These results suggest that ChondroT will be able to apply to the treatment of osteoarthritis through continuous research and development. (J Korean Med Rehab 2015;25(4):55-63) Copyright 2015 The Society of Korean Medicine Rehabilitation Key words ChondroT, Osteoarthritis, Domestic trend 서론»»» 나이, 성별, 과체중또는스트레스등이위험인자로작용하는골관절염은퇴행성관절질환 (degenerative joint disease) 이라고도하며, 국소관절의점진적연골소실및이차적변화를야기하는질환이다 1). 국소관절의통증이가장흔한증상이며, 질병이진행됨에따라관절액증가로인한부종, 운동장애, 연관통등의증상이발생하기도한다 2). 골관절염의진행을막을수있는방법은아직없으며 1), 보존적으로비약물치료를기본적으로실시하되필요시비스테로이드성항염제 (non-steroidal anti-inflammatory drug, NSAID), 아스피린등의약물과관절내스테로이드주사치료를병행하기도하고 3), 의학적금기사항이없고기능이심각하게저하되어있는경우는수술적치료를고려하게된다 1). 하지만스테로이드주사는체중부하관절에서는두번이상은피해야하며, 상기경구약은간, 신장, 위장부작용이흔하게발생하는데 3), 골관절염의가장중요한위험인자가노화 1) 라는점을감안하였을때, 치료 55

2 배길준 정지원 송민영 김태광 김선종 외적인부작용을고려하지않을수없다. 한의학적으로골관절염은痺症의범주에속하여膝痛, 膝疼痛, 膝腫, 鶴膝風, 膝痺등으로표현되며, 슬관절, 근육등에疼痛, 疝痛, 痲木등의증상과관절의屈伸不利등을수반하게된다 4). 골관절염에대한치료는한의학적으로도많은연구가이루어지고있는데, ChondroT는강활, 당귀, 금은화, 위령선, 황백으로구성되어현재관절질환치료를위해개발중에있는처방으로 治風濕相搏, 肢節腫痛, 不可屈伸 의효능이있는대강활탕 5) 과 治濕熱脚氣腫痛諸症 의효능이있는청열사습탕 5) 을합방하여백출, 소엽, 빈랑, 지각, 향부자를去하고등심, 조각자, 금은화, 포공영을加한후최적화과정을거쳐선정한 5개약제로구성되었다. 선정과정에서약제구성의최적화를위해전통중의학통합데이터베이스 (traditional chinese medicine integrated database, TCMID) 를통해개별한약재의성분데이터를수집하고, 비교독성유전체학데이터베이스 (comparative toxicogenomics database, CTD) 를통해수집한성분들이표적하고있는유전자데이터를수집하였으며, 인간유전자데이터베이스 (genecards database) 를통해관절염에관련된유전자를수집하여개별한약재와관절염연관유전자들사이의관계성을파악하는유전자정보처리 (bio-informatics) 기법을이용하였다. 처방구성을살펴보면강활은散寒, 祛風, 除濕, 止痛의효능이있어風寒濕邪로인한關節疼痛을치료할수있고, 당귀는甘溫한성미를가지고있어祛風濕藥과배합하여風濕痺痛을치료한다고하였으며, 금은화는淸熱解毒의효능이있어소염작용을, 위령선은辛散溫通하고性急善走하여風濕痺痛, 筋脈拘攣, 關節屈伸不利, 肢體痲木등을치료할수있고, 황백은淸熱燥濕, 瀉火解毒하는작용이있다고하여 6), 개별약물을효과적으로응용한다면골관절염의치료에효과가있을것으로사료된다. 이에저자는관절질환치료제로개발연구중에있는 ChondroT 의개별약물들과관련된골관절염연구들을분석함으로써본약물들의골관절염치료근거를확립하기위해본연구를진행하였다. 대상및방법»»» 1. 논문검색자료검색은전통의학정보포털시스템 ( re.kr), 국가과학기술정보센터 ( 한국전통지식포탈 ( 한국학술정보 ( 한국교육학술정보원 ( riss.kr) 의 5개데이터베이스를이용하여발표시기및유형등을고려하지않고 ChondroT 의구성약물인 강활, 당귀, 위령선, 금은화, 황백 의검색어로각각진행하였다. 2. 연구대상선별주저자를제외한 3인의독립된저자가 1개또는 2개의구성약물을담당하여각각의검색어로검색된논문중한의학학술지의논문을선별한후중복되는논문을배제하는 1차선별과정을진행하였다. 주저자는 1차선별과정후남은논문들의제목및초록을검토하여 관절, 염증, 퇴행, 항염 등골관절염과유관한주제어를포함한논문및위주제와유관한논문을선별하는과정을진행하여약재별로논문을최종분류하였다. 위약재가단일로사용되지않은논문, 종설논문등단일약재의효능을조사하기에적합하지않은논문은연구대상에서배제하였다. 결과»»» 1. 연구대상선정결과 5개의데이터베이스검색결과데이터베이스간의중복된논문을포함하여 강활 의검색어로총 385건, 당귀 의검색어로총 1,722건, 위령선 의검색어로총 84건, 금은화 의검색으로총 332건, 황백 의검색어로총 769건이검색되었으며, 위의선별과정을통해최종적으로 강활 2편, 당귀 5편, 위령선 3편, 금은화 6편, 황백 2편등총 18편의논문을선정하였다 (Fig. 1). 56 J Korean Med Rehab 2015;25(4):55-63

3 ChondroT 구성약물의골관절염관련국내연구동향 - 한의학학술지를중심으로 Fig. 1. Flow chart of the trial selection process (G: Ostericii Radix, D: Angelica Gigas Nakai, W: Clematidis Radix, K: Lonicerae Flos, H: Phellodendri Cortex). Table I. Summary of Osteoarthritis-related Research on Each Constituent Herb of ChondroT No. First Author (Year) 1 7) Park CW (1998) 2 8) Jang SI (2002) 3 9) Yu S (2004) 4 10) Lee DE (2005) 5 11) Yang KJ (2005) 6 12) Yun YG (2007) 7 13) Kim JY (2007) 8 14) Park HJ (2008) 9 15) Kim CM (2009) 10 16) Ahn SH (2010) 11 17) Kim HS (2010) 12 18) Ryu MS (2010) 13 19) Choi YJ (2011) 14 20) Yun KJ (2012) 15 21) Lee JS (2012) 16 22) Kang YG (2013) 17 23) Han HS (2013) 18 24) Han HS (2013) Title The effect of Phellodendri Cortex aqua - acpuncture pretreatment at rabit knee joint arthritis on the reduce of inflamation content induced by lipopoly saccharide Anti-Inflammatory Effect of Ethanol Extract of Angelica uchiyamana in Activated Murine RAW macrophages Effect of CR (Clematidis Radix) on Anti-Inflammatory, Analgesic and Antipyretic in Animal Model. Inhibition of Lipopolysaccharide-Inducible Nitric Oxide Synthase, TNF-α, IL-1β and COX-2 Expression by Flower and Whole Plant of Lonicera japonica Effects of Clematis mandshurica Rupr. on Nitric Oxide Synthase in the Periaqueductal Gray of Collagenase-induced Rat Osteoarthritis Model Inhibitory Effect of Aqueous Extract from Lonicera japonica Flower on LPS-induced Inflammatory Mediators in RAW Macrophages A Study on the Effect of Herbal-acupuncture with Phellodendri Cortex Solution on Collagen-induced Arthritis in DBA/1J Mice Inhibitory Effect of Extract from Ostericum koreanum on LPS-induced Proinflammatory Cytokines Production in RAW264.7 Cells The Effects of Different Extracts of Ostericum koreanum on the Production of Inflammatory Mediators in LPS-stimulated RAW264.7 Cells Lonicerae Flos Inhibited COX-2 and MMP-9 in LPS Induced Arthritis of Mouse through Regulation of MIF Effects of flos lonicerae water extract on anti-rheumatiod arthritis The Effect of Angelica gigas NAKAI Pharmacopuncture at ST36 and BL23 on Freund s Adjuvant Arthritis in Rats Effects of Angelicae Gigantis Radix pharmacopuncture on Nitric Oxide and Prostaglandin E2 Production in Macrophage Effects of Hot Aqueous and Ethanol Extract from Lonicera japonica Flos on NO and PGE 2 in Macrophage The Effect of Clematidis Radix Herbal-acupuncture Solution, on Collagen, Adjuvant, Lipopolysaccharide and Phospholipase A2 Induced Rheumatoid Arthritis in Mice A Study on the Inhibitory Effect and Mechanism of Lonicera Japonica on Type I Interferon Anti-inflammatory Effect of Angelicae Gigantis Radix Water Extract on LPS-stimulated Mouse Macrophages Anti-inflammatory Effect of Angelicae acutilobae Radix Water Extract on LPS-stimulated Mouse Macrophages Journal Journal of Korean Acupuncture&Moxibustion Society Korean Journal of Oriental Medical Prescription Journal of Korean Medicine Rehabilitation Korean Journal of Oriental Physiology and Pathology Korean Journal of Meridian&Acupoint Korean Journal of Meridian&Acupoint Korean Journal of Oriental Physiology and Pathology Korean Journal of Oriental Medical Prescription Journal of Korean Acupuncture&Moxibustion Society Journal of Korean of Pharmacopuncture Journal of Korean Acupuncture&Moxibustion Society Journal of Korean Acupuncture&Moxibustion Society Journal of Korean Obstet Gynecol 57

4 배길준 정지원 송민영 김태광 김선종 2. 연도별분류 본연구에선정된 18편의논문은각각 1998년도에 1 편, 2002년도에 1편, 2004년도에 1편, 2005년도에 2편, 2007년도에 2편, 2008년도에 1편, 2009년도에 1편, 2010 년도에 3편, 2011년도에 1편, 2012년도에 2편, 2013년도에 3편이발표되었다 (Table I). 3. 학회지별분류 선정된논문은 18편으로대한본초학회지에서 5편, 대한침구의학회지에서 4편, 대한방제학회지, 동의생리병리학회지, 경락경혈학회지에서각각 2편, 한방재활의학과학회지, 대한약침학회지, 한방부인과학회지에서각각 1편씩발표되었는데, 학술지별로분류한결과는다음과같다 (Table I). 4. 약재별분류 1) 강활 강활의골관절염관련논문은총 2편으로모두세포실험논문이었다. 두논문모두쥐의대식세포주인 RAW264.7 세포에서그람음성균의외막성분인 lipopolysaccharide (LPS) 에의해유도된염증물질에대한효과를알아본실험이었다. 박 14) 등은 nitric oxide (NO) 생성에미치는영향, cytokine 발현에대한영향, mitogen-activated protein kinases (MAPKs) 의발현억제효과, endotoxin shock 의억제효과등에대한실험을진행하였으며, 김 15) 등은 NO, prostaglandin E 2 (PGE 2 ) 생성에대한효과, inducible nitric oxide synthease (inos) 발현에대한효과등에대한실험을진행하였다 (Table II). Table II. Summary of Osteoarthritis-related Effects on Ostericii Radix 1 14) RAW264.7 cells Inhibit NO, TNF-α, IL-6, IL-10 Inhibit p38, ERK, JNK 2 15) RAW264.7 cells Inhibit NO, PGE 2 production Inhibit inos NO: nitric oxide, TNF: tumor necrosis factor, IL: interleukin, ERK: extracellular signal-regulated kinase, JNK: c-jun NH2- terminal kinase, PGE 2: prostaglandin E 2, inos: inducible nitric oxide synthease. 2) 당귀 당귀의골관절염관련논문은총 5편으로 4편의세포실험과 1편의동물실험이있었으며, 2편은당귀약침액을, 3편은당귀추출물을사용한실험이었다. 류 18) 등은당귀약침을 freund s adjuvant 로유발된백서의관절염모델에주입하여부종지수, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) 등의변화에대해, 최 19) 등은당귀약침액이대식세포에서 NO 및 PGE2 생성에미치는영향에대해연구하였다. 당귀추출물에대한연구를살펴보면장 8) 등은 RAW264.7 세포에서 NO 및 TNFα의생성과 inos, cyclooxygenase-2 (COX-2) 발현에대한효과를살펴보았고, 한 23,24) 은두편의논문에서각각참당귀와일당귀의대식세포에대한효능을실험하였다 (Table III). 3) 위령선 위령선의골관절염관련논문은총 3편으로 2편의동물실험과 1편의동물, 세포동시실험이있었다. 유 9) 등은 carrageenan 으로유발된관절염모델흰쥐에약물을경구투여하여혈액검사및진통, 해열작용에대한실험을진행하였고, 양 11) 등은 collagenase 로유발된관절염모델흰쥐에위령선약침을투여하여 nitric oxide synthase (NOS) 와 neuronal NOS (nnos) 발현에미치는영향을알아보았 Table III. Summary of Osteoarthritis-related Effects on Angelica Gigas Nakai 1 8) RAW264.7 cells Inhibit NO, PGE 2 production 2 18) Adjuvant-induced arthritis rats Decrease edema rate Increase IFN-γ, TNF-α 3 19) RAW264.7 cells Inhibit NO, PGE 2 production Suppress inos, COX-2 expression 4 23) RAW264.7 cells Inhibit TNF-α, MIP-1α, G-CSF, M-CSF, VEGF, MIP-1β, MIP-2, GM-CSF, IL-6, IL ) RAW264.7 cells Inhibit IL-6, TNF-α, G-CSF, GM-CSF, MIP-1α IFN: interferon, TNF: tumor necrosis factor, NO: nitric oxide, PGE 2: prostaglandin E 2, inos: inducible nitric oxide synthease, COX: cyclooxygenase, MIP: macrophage inflammatory protein, G-CSF: granulocyte colony-stimulating factor, M-CSF: macrophage colony-stimulating factor, GM-CSF: granulocyte macrophage colony-stimulating factor, IL: interleukin, VEGF: vascular endothelial growth factor. 58 J Korean Med Rehab 2015;25(4):55-63

5 ChondroT 구성약물의골관절염관련국내연구동향 - 한의학학술지를중심으로 Table IV. Summary of Osteoarthritis-related Effects on Clematidis Radix 1 9) Carrageenan-induced arthritis rats 2 11) Collagenase-induced arthritis rats 3 21) RAW264.7 cells Collagen, adjuvant, LPS, PLA2 induced arthritis Decrease CRP, ESR, WBC Decrease frequency of writhing syndrome Increase threshold of pain Suppress nnos, NOS expression Reduce arthritis index Suppress PLA 2, COX-2 expression Decrease PGE 2 production nnos: neuronal nitric oxide synthase, NOS: nitric oxide synthase, PLA 2: phospholipase A 2, COX: cyclooxygenase, PGE 2: prostaglandin E 2. 다. 그리고이 21) 등은 RAW264.7 세포와 type II collagen, adjuvant, LPS, phospholipase A 2 (PLA 2 ) 유발모델흰쥐를이용하였다 (Table IV). 4) 금은화 금은화의골관절염관련논문은총 6편이었다. 6편모두 LPS로유도된 RAW264.7 세포및관절염모델흰쥐를이용하였으며, 특히김 17) 등은 collagen 유발관절염모델흰쥐에동시에실험을진행하였다 (Table V). 5) 황백 황백을투여한골관절염관련논문은총 2편으로, 모두동물실험이었으며황백약침을이용하였다. 박 7) 등은 LPS 유도관절염모델토끼를사용하였고, 김 13) 등은 collagen 유도관절염모델흰쥐를이용하였으며그결과는다음과같다 (Table VI). 고찰및결론»»» 성인에게서가장흔한관절질환인골관절염은퇴행성관절염 (degenerative arthritis), 퇴행성관절질환 (degenerative joint disease), 변형성관절증 (osteoarthrosis) 이라고도하며관절의변형또는골연골부의과잉골형성을특징으로하여관절통, 경직, 부종, 관절염발음등의증상을나타내는질환이다 25). 원인으로는연령, 성별, 유전, 영양상태 Table V. Summary of Osteoarthritis-related Effects on Lonicerae Flos 1 10) RAW264.7 cells Inhibit NO, inos, COX-2, TNF-α, IL-1β, IL ) RAW264.7 cells Reduce NO, PGE 2, TNF-α, IL-1, IL-6, COX ) LPS induced Decrease MIF, COX-2, MMP-9 arthritis mouse 4 17) RAW264.7 cells Collagen induced arthiritis mouse Inhibit NO, IL-1β, IL-6, TNF-α, PGE 2, inos, COX-2 Reduce arthritis incidence, index, paw edema 5 20) RAW264.7 cells Suppress NO, PGE 2 production 6 22) LPS induced macrophage Inhibit type Ⅰ IFN, IRF-1, 3, 7 Reduce STAT-1, 3 activation NO: nitric oxide, inos: inducible nitric oxide synthease, COX: cyclooxygenase, TNF: tumor necrosis factor, IL: interleukin, MIF: migration inhibitory factor, MMP: matrix metalloproteinase, IFN: interferon, IRF: interferon regulatory factor, STAT: signal transducers and activators of transcription. Table VI. Summary of Osteoarthritis-related Effects on Phellodendri Cortex 1 7) LPS induced rabbit Inhibit IL-1β, leucocyte, loss of proteoglycan 2 13) Collagen induced mice Decrease arthritis index, incidence of arthritis, joint edema Decrease IL-1β, IL-6, IFN IL: interleukin, IFN: interferon. 등의전신요소와비만, 근육약화, 관절과다사용등의외부요소가있으며, 영상의학적으로관절강간격의감소, 골경화, 압박을받는부위의골낭종과압박을받지않는부위의골증식등의소견을보이게된다 26). 골관절염은연골에기계적인자극이가해졌을때연골기질의손상및변화가생기게되어 interleukin (IL)-1, TNF-α 등세포질분해효소에의해파괴와재형성과정이이루어지며, matrix metalloproteinase (MMPs), IL-8, IL-6, PGE 2, NO 등의분비를증가시키게되어 1) proteoglycan, type II collagen 등의농도가감소하면서골세포사멸이발생하게되며, 이러한과정중에관절강직감, 점진적운동장애가발생하며, 관절부위통증, 종창, 발열등의증상을보이게된다 27). 골관절염의치료는비약물적치료, 약물치료, 수술적 59

6 배길준 정지원 송민영 김태광 김선종 치료등으로나뉘게되는데, 약물치료로는아세트아미노펜이 1차약물로사용되며, 그외에 naproxen, aceclofenac, celecoxib 등의 NSAID, oxymorphone, oxycodone, oxytrex 와같은마약성진통제등의약물이나 hyaluronic acid와같은관절내주사제등이의료진의진단하에선택적으로사용되고있고, 통증과기능장애가심한환자에게는필요시수술적치료를시행하게된다 28). 하지만세계적으로 60대이상남성의 9.6%, 여성의 18.0% 가골관절염의증후를나타내는바와같이 27) 연령이골관절염의가장큰위험인자라는것을고려한다면, 60세이상의고령자에게서상부위장관부작용이일어날가능성이높은 NSAID 나심혈관계부작용이생길수있는선택적 COX-2 억제제, 오심, 구토, 중독, 어지러움등의부작용을가지고있는마약성진통제등의약물 28) 은신중히사용되어야할것이며, 부작용을최소화하고보다나은치료효과를나타내기위한연구역시지속적으로이루어지고있다. 한의학에서는골관절염을痺證으로분류하여榮衛失調, 腠理空疎, 正氣虛弱시風寒濕熱의邪氣가체내에침입하여관절에凝滯되어발생하며 29) 이로인해關節酸楚, 疼痛, 重着, 腫大, 활동장애등의특징을가진痺證의병증이나타나게된다 25). 한의학적으로도골관절염의치료에대한다양한연구가이루어지고있는데, 여 30) 등의국내연구동향에대한분석을살펴보면가장큰비중을차지하는약침연구와더불어침, 약물, 태극권치료법등다양한치료방법의연구가진행중인것을알수있으며, 김 31) 등의보고를보아도골관절염에대한연구는지속적으로증가추세인것을알수있다. 특히최근에는진통, 소염등에대한치료에서연골세포보호및재생에대한연구로의전환이이루어지고있는추세로 30) 근본적인질병치료에대한연구가활발히이루어지고있음을알수있다. ChondroT 는대강활탕과청열사습탕을합방하여백출, 소엽, 빈랑, 지각, 향부자를去하고등심, 조각자, 금은화, 포공영을加한후최적화과정을거쳐선정한 5개약제로구성되어현재염증성관절질환치료를위해개발중인처방이다. 5개약재로최적화하기전에 18종 ( 강활, 창출, 당귀, 독활, 모과, 목통, 위령선, 적복령, 적작약, 진피, 택사, 등심, 조각자, 금은화, 포공영, 감초, 방기, 황백 ) 으로구성된한약제제는동신대학교부속한방병원에서치료효능에대한증례를수집및분석하였고, 정 32) 등의연구 를통해효능및약리기전에대한연구를진행하였다. 그리고 18종의한약재들이관절염과연관성있는유전자들에대해어느정도의유의성이있는지판단하기위해전통중의학통합데이터베이스를통해당귀는 phenol 외 163개, 강활은 guaiol 외 135개, 위령선은 anemonol 외 89개등각각한약재의성분데이터를수집하고비교독성유전체학데이터베이스를통해당귀 10,533 개, 강활 5,904개, 금은화 5,249개등의각각한약재의성분이표적하는유전자를추출하였으며, 인간유전자데이터베이스를통해 TNF-α, COX-2, IL-6, NF-κB 등관절염관련유전자 1,811개를추출한후관절염을유발시키는핵심유전자 15개를선정하여 18종의한약재들이표적하고있는유전자를확인후최종적으로가장유의성이있다고판단되는 5개약제를선정하게되었다. 하지만위의선정과정은단순히표적되는유전자들을추출하였을뿐, 해당유전자에대한구체적작용까지는알아내기어려운단점이있다. 이에본연구는선정된 5개한약제제가골관절염과관련하여국내에서이루어진연구현황을분석하여처방구성의근거를마련하고자하였다. 연구대상선정을위해전통의학정보포털시스템, 국가과학기술정보센터, 한국전통지식포탈, 한국학술정보, 한국교육학술정보원의 5개데이터베이스를이용하여 5개약제에대한논문을수집한후선별과정을거쳐강활 2 편, 당귀 5편, 위령선 3편, 금은화 6편, 황백 2편등총 18편의논문을선정하였다. 선정된 18편의논문은모두실험논문으로, 이는한의학의특성상단미제는투여하는경우가적기때문에임상적으로위단미제들을연구할기회는적었을것으로생각된다. 18편의논문중당귀 2편, 위령선 2편, 황백 2편등총 6편은약침에대한연구로, 약침의경우홍화약침, 녹용약침등단미제가사용되는경우도있기때문에추후추가적인연구와더불어임상연구도진행된다면한의학적골관절염치료의확장에도움이될것이다. 강활논문 2편은모두세포실험논문으로, 쥐의대식세포주인 RAW264.7 세포에서 LPS에의해유도된염증물질에대한효과를알아본실험이었다. 그람음성세균세포외막의성분인 LPS는 TNF-α, IL-1β, IL-6 등을분비하도록세포를자극하여세균의침입을방어하도록도와주지만이러한분자들의과도한분비는조직손상, 폐혈증등자가면역질환을야기하게된다 14). 박 14) 등은강활추출 60 J Korean Med Rehab 2015;25(4):55-63

7 ChondroT 구성약물의골관절염관련국내연구동향 - 한의학학술지를중심으로 물의항염증효과를실험한결과 NO 생산의억제, TNF-α, IL-6, IL-10 등 cytokine 의생성억제, extracellular signal-regulated kinase (ERK), c-jun NH2-terminal kinase (JNK), p38의인산화가억제됨을확인하였다. ERK, JNK, p38은세포의다양한생물학적기능을조절하는 MAPKs 의구성요소들로이들의인산화를저해하여결론적으로 NO의생산성을줄여항염증효과를보인다고사료된다 14). 김 15) 등도위의모델에서 NO와 PGE 2 의생성이유의하게억제됨을확인하였다. NO의과도한분비는세포독성을통해조직손상을유발하며, PGE 2 는조직손상이일어나는부위에생성되어통증역치를감소시키게된다 15). 당귀논문은총 5편으로약침을사용한논문 2편과추출물을사용한논문 3편이있다. 류 18) 등은당귀약침을 adjuvant 유발흰쥐에주입하여부종지수의감소, IFN-γ, TNF-α의증가효과를보였다. IFN-γ는대식세포활성화 cytokine 으로염증이있는곳에서단핵구수를증가시키는것으로알려져있으며, TNF-α는연골을파괴하는단백분해효소를생성하게하고, 국소골흡수부위에모여있는파골세포를자극하여국소광물질제거에기여하는것으로알려져 18) 당귀약침주입을통한이들의증가를통해항염증과정이진행됨을관찰하였다. 최 19) 등은당귀약침액이 NO와 PGE 2 의생성을억제함을관찰하였고, 장 8) 은 NO, COX-2, TNF-α 등염증매개물질을억제함을관찰하였다. 한 23,24) 은참당귀와일당귀를분류하여진행한실험을통해참당귀는 TNF-α, macrophage inflammatory protein (MIP)-1α, granulocyte (G)-CSF, macrophage (M)-CSF, vascular endothelial growth factor (VEGF), MIP-1β, MIP-2, granulocyte macrophage (GM)-CSF, IL-6, IL-10의생성증가를억제하였고일당귀는 IL-6, TNFα, G-CSF, GM-CSF, MIP-1α 의생성증가를억제함을확인하였다. MIP-1α 는호중구침윤을촉진하여염증반응을증가시키며, G-CSF 는백혈구생성을촉진하여혈중조혈모세포의수를증가시키고, M-CSF 는지방단백질의일종으로조혈인자로서의작용과단핵구의항종양활성증폭등의작용을하며, VEGF는혈관내피세포에서발현되는유사분열촉진인자이다 23,24). MIP-1β 는면역반응과염증반응에작용을하게되며, MIP-2 는호중구의모집과정에서역할을담당하게되고, GM-CSF 는감염부위에대식세포가집락화되도록자극하는역할을한다 23,24). 3편의위령선논문을살펴보면, 유 9) 등은 carrageenan 유발관절염흰쥐에위령선을경구투여하여진통, 해열효과및 CRP, ESR, WBC의감소가있음을관찰하였으며, 양 11) 등은 collagen 유도관절염흰쥐에서 NOS 및 nnos 의발현을억제하였음을관찰하였다. 이 21) 등은 collagen 유도관절염흰쥐에서위령선약침처치가관절염지수의감소를보이며 adjuvant 유발관절염흰쥐에서또한관절염억제효과를보임을관찰하였으며, COX-2 의활성역시억제하는것으로나타났다. 6편의금은화논문은모두 LPS로유도된 RAW264.7 세포및관절염모델흰쥐를이용하였으며, 이 10) 등은 NO, inos, COX-2, TNF-α, IL-1β, IL-6의생성을억제함을, 윤 12) 등은 NO, PGE 2, TNF-α, IL-1, IL-6, COX-2 등의감소를, 안 16) 등은 migration inhibitory factor (MIF), COX-2, matrix metalloproteinase (MMP)-9의감소를, 윤 20) 등은 NO, PGE 2 의생성을억제함을, 강 22) 등은 type I interferon (IFN), interferon regulatory factor (IRF)-1, 3, 7을억제하고 signal transducers and activators of transcription (STAT)-1, 3의활성을감소시킴을관찰하였으며, 김 17) 등은 NO, IL-1β, IL-6, TNF-α, PGE 2, inos, COX-2 의억제를확인함과동시에 collagen 유도관절염흰쥐에서관절염지수및부종지수의감소를동시에확인하였다. 황백약침을이용한 2편의논문에서박 7) 등은 LPS로유도된토끼모델을통해 IL-1β의발현과 proteoglycan 의감소를억제함을관찰하였으며, 김등은 collagen 유도관절염흰쥐에서관절염지수및관절부종의감소, IL-1β, IL-6, IFN의농도감소를관찰하였다. 이와같이 ChondroT 의구성약물의골관절염관련국내연구를살펴본결과, 5개약물모두세포실험또는동물실험에서특정염증매개인자에유의성있는보고가있음을확인할수있었다. 이러한결과는위 5개약물을적절히활용한다면골관절염의치료에유효한작용을보일수도있다는최소한의근거가될수있을것이다. 하지만이번분석은골관절염관련논문만분석하여연구범위가다소편협된부분이있어추후에위약물들에대한다른효능에대한분석역시필요할것으로보이며, 포제또는기원에따라효능의변화가생길수있기에이에대한구체적인연구또한필요할것으로사료된다. 더불어약재각각의氣味, 藥性및歸經등에차이가있기때문에 ChondroT 복합처방은단미제와달리약재의配伍등을적절히고려하여최대의약효를내도록지속적인연구가 61

8 배길준 정지원 송민영 김태광 김선종 이루어져야할것이며, 향후실험연구및임상연구를통해효과에대한충분한검증이이루어져야할것이다. References»»» 1. The Korean Orthopaedic Association. Orthopaedics 7th edition. Seoul : New medical publisher. 2013: Kung SE, Oh MS. Effects of Sayeok-tang on Papain- Induced Osteoarthritis in Mice. Korean J. of Oriental Physiology and Pathology. 2013;27(2): American Academy of Orthopaedic Surgeons. Essentials of Musculaoskeletal Care. Seoul : Hanwoori. 2009: Kim DH, Kang SI, Song MY, Choi JB, Bae KJ, Han JS, Yang MS, Sin YJ. Effects of Bangkeehwangkee-tang (fangjihuangqi-tang) Treatment on the Monosodium Iodoacetate-induced Osteoarthritis in Rats. J. of Korean Medicine Rehabilitation. 2014;24(2): Heo J. Donguibogam. Seoul : BUBIN PUBLISHERS CO. 2005:1431, Korean Medicine University Herbology Editing Commission. Herbology. Seoul : Younglimsa. 2008:160, 630, 241, 306, Park CW, Kim GS. The effect of Phellodendri Cortex aqua - acpuncture pretreatment at rabit knee joint arthritis on the reduce of inflamation content induced by lipopoly saccharide. J. of Korean Acupuncture&Moxibustion Society. 1998;15(1): Jang SI, Kim HJ, Hwang KM, Pae HO, Yun YG, Chung HT, Kim YC. Anti-Inflammatory Effect of Ethanol Extract of Angelica uchiyamana in Activated Murine RAW macrophages. Korean J. of Oriental Medical Prescription. 2002;10(2): Yu S, Keum DH, Lee MJ. Effect of CR(Clematidis Radix) on Anti-Inflammatory, Analgesic and Antipyretic in Animal Model. J. of Korean Medicine Rehabilitation. 2004;14(2): Lee DE, Lee JR, Kim YW, Kwon YK, Byun SH, Shin SW, Suh SI, Kwon TK, Byun JS, Kim SC. Inhibition of Lipopolysaccharide-Inducible Nitric Oxide Synthase, TNFα, IL-1β and COX-2 Expression by Flower and Whole Plant of Lonicera japonica. Korean J. of Oriental Physiology and Pathology. 2005;19(2): Yang KJ, Kim SJ, Seo IB, Park SK, Kim JS, Seo JC, Choi SM, Lee HJ, Kim EH. Effects of Clematis mandshurica Rupr. on Nitric Oxide Synthase in the Periaqueductal Gray of Collagenase-induced Rat Osteoarthritis Model. Korean J. of Meridian&Acupoint. 2005;22(4): Yun YG, Kim GM, Lee SJ, Ryu SH, Jang SI. Inhibitory Effect of Aqueous Extract from Lonicera japonica Flower on LPS-induced Inflammatory Mediators in RAW Macrophages. Korean J. of Herbology. 2007;22(3): Kim JY, Lee H. A Study on the Effect of Herbal-acupuncture with Phellodendri Cortex Solution on Collagen-induced Arthritis in DBA/1J Mice. Korean J. of Meridian&Acupoint. 2007;24(2): Park HJ, Bae GS, Kim DY, Seo SW, Park KB, Kim BJ, Song JM, Lee KY, Na C, Shin BC, Park SJ, Song HJ, Hwang SY. Inhibitory Effect of Extract from Ostericum koreanum on LPS-induced Proinflammatory Cytokines Production in RAW264.7 Cells. Korean J. of Herbology. 2008;23(3): Kim CM, Park YK. The Effects of Different Extracts of Ostericum koreanum on the Production of Inflammatory Mediators in LPS-stimulated RAW264.7 Cells. Korean J. of Herbology. 2009;24(1): Ahn SH, Kim HH. Lonicerae Flos Inhibited COX-2 and MMP-9 in LPS Induced Arthritis of Mouse through Regulation of MIF. Korean J. of Oriental Physiology and Pathology. 2010;24(2): Kim HS, Ki HP, Lee JS, Yun YG. Effects of flos lonicerae water extract on anti-rheumatiod arthritis. Korean J. of Oriental Medical Prescription. 2010;18(2): Ryu MS, Yun YC, Kim JH. The Effect of Angelica gigas NAKAI Pharmacopuncture at ST36 and BL23 on Freund s Adjuvant Arthritis in Rats. J. of Korean Acupuncture& Moxibustion Society. 2010;27(5): Choi YJ, Roh JD. Effects of Angelicae Gigantis Radix pharmacopuncture on Nitric Oxide and Prostaglandin E2 Production in Macrophage. J. of Korean Pharmacopuncture. 2011;14(3): Yun KJ, Lee EY. Effects of Hot Aqueous and Ethanol Extract from Lonicera japonica Flos on NO and PGE₂ in Macrophage. J. of Korean Acupuncture&Moxibustion Society. 2012;29(1): Lee JS, Kim KH, Lee SD, Kim KS. The Effect of Clematidis Radix Herbal-acupuncture Solution, on Collagen, Adjuvant, Lipopolysaccharide and Phospholipase A2 Induced Rheumatoid Arthritis in Mice. J. of Korean Acupuncture& Moxibustion Society. 2012;29(1): Kang YG, Ryu IH, Kim SB, Choi CM, Seo YJ, Cho HB. A Study on the Inhibitory Effect and Mechanism of Lonicera Japonica on Type I Interferon. J. of Korean Obstet Gynecol. 2013;26(2): Han HS. Anti-inflammatory Effect of Angelicae Gigantis Radix Water Extract on LPS-stimulated Mouse Macrophages. Korean J. of Herbology. 2013;28(5): Han HS. Anti-inflammatory Effect of Angelicae acutilobae Radix Water Extract on LPS-stimulated Mouse Macrophages. Korean J. of Herbology. 2013;28(6): The Society of Korean Medicine Rehabilitation. Korean Medicine Rehabilitation the 4th edition. Seoul : Koonja 62 J Korean Med Rehab 2015;25(4):55-63

9 ChondroT 구성약물의골관절염관련국내연구동향 - 한의학학술지를중심으로 publisher. 2015: Kang HS, Hong SH, Kang CH. Musculoskeletal radiology. Seoul : Panmun education. 2014: Lee EJ, Oh MS. Effects of Keonbodan on MIA-Induced Osteoarthritis in Rat. J. of Korean Medicine Rehabilitation. 2014;24(2): Yoon CH. Osteoarthritis Update. The Korean J. of Internal Medicine. 2012;82(2): Kook KH, Oh MS. Effects of Leejung-tang on MIA- Induced Osteoarthritis Rat. J. of Korean Medicine Rehabilitation. 2014;24(1): Yoh SB, Sul JU, Shin MS. Research Trends on the Treatment of Knee Osteoarthritis in Korean Medicine. Korean J. of Acupuncture. 2011;28(1): Kim TY, Kim JH, Park JH, Lee JK, Han C, Kum CJ, Oh JW. The Domestic Trends of Traditional Korean Medicine Treatments on Degenerative Knee Arthritis. The J. of Korea CHUNA Manual Medicine for Spine&Nerves. 2014; 9(2): Jeoung BR, Lee KD, Na CS, Kim YE, Kim BA, Kim YR. Ganghwaljetongyeum, an anti-arthritic remedy, attenuates synoviocyte proliferation and reduces the production of proinflammatory mediators in macrophages: the therapeutic effect of GHJTY on rheumatoid arthritis. BMC Complementary and Alternative Medicine. 2013;13:

139~144 ¿À°ø¾àÄ§

139~144 ¿À°ø¾àÄ§ 2 139 DOI : 10.3831/KPI.2010.13.2.139 2 Received : 10. 04. 08 Revised : 10. 04. 26 Two Case Report on Wrist Ganglion Treated with Scolopendrid Pharmacopuncture Accepted : 10. 05. 04 Key Words: Wrist Ganglion,