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1 골관절염의치료에서 COX-2 선택적비스테로이드성소염진통제의이용 성균관대학교의과대학삼성서울병원정형외과학교실 송영준ㆍ하철원 The Use of COX-2 Selective Nonsteroidal Anti-inflammatory Drugs for the Treatment of Osteoarthritis Young-Joon Song, M.D. and Chul-Won Ha, M.D. Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Nonsteroidal anti-inflammatory drugs (NSAIDs), are characterized by their anti-inflammatory, analgesic, and antipyretic activities; they have been widely used for the management of acute pain and chronic inflammation. The mechanism of action of NSAIDs is inhibition of prostaglandin biosynthesis. Inflammatory prostaglandins are primarily derived from COX-2, while the prostaglandins formed by COX-1 have in general a more homeostatic role. Based on their selectivity for COX-1 or COX-2, NSAIDs are classified into non-selective NSAIDs and COX-2 selective NSAIDs. Non-selective NSAIDs and COX-2 selective NSAIDs have similar effects on pain relief and inflammation. One major problem associated with the use of non-selective NSAIDs is their adverse effects on the gastrointestinal tract, caused by inhibition of COX-1. Compared with non-selective NSAIDS, the main advantage of COX-2 selective NSAIDs is reduced gastrointestinal complications. Reviews have suggested that COX-2 selective NSAIDs increase the risk of cardiovascular events; however, cardiovascular risk may vary among the selective NSAIDs. Because of their anti-inflammatory properties, the use of NSAIDs is essential for the relief of pain and the symptoms associated with inflammatory conditions such as active osteoarthritis. When NSAIDs are prescribed, age, additional medication such as aspirin, gastrointestinal and cardiovascular status, and co-morbidity must be taken into account. COX-2 selective NSAIDs have minimal effects on platelet function and thus, can also be used for pre and postoperative pain control in patients with osteoarthritis waiting for the surgery. Key Words: NSAID, COX-2 selective, Osteoarthritis, Treatment COX-2 선택적소염진통제개발배경 통신저자 : 하철원 , 서울시강남구일원동 50번지성균관대학교의과대학삼성서울병원정형외과 TEL: , FAX: hacw@skku.edu 접수일 : 2009년 5월 9일수정일 : 2009년 5월 11일게재허가일 : 2009년 5월 12일 비스테로이드성소염진통제 (Nonsteroidal anti-inflammatory drug; NSAID; 이하소염진통제 ) 는항염 (anti-inflammatory), 진통 (analgesics), 해열 (antipyretic) 작용을공통된특징으로하는화학적으로이질적인화합물군이다 년최초의소염진통제인아스피린 (acetylsalicylic acid) 이출시된이래 40여종이넘는많은소염진통제들이개발되었으며, 현재급성통증및만성염증관리를위해광범 84

2 송영준ㆍ하철원 : 골관절염의치료에서 COX-2 선택적비스테로이드성소염진통제의이용 85 위하게사용되고있다 43,45). 소염진통제의근본적인작용기전은프로스타글란딘 (prostaglandin) 의생성억제이며프로스타글란딘은 arachidonic acid(aa) 로부터 cyclooxygenase (COX) 42) 라는효소를통해생성된다. 우리몸에는 COX-1 과 COX-2 두가지아형 (isoform) 이존재하는데 15,21) 이들효소의선택성에따라소염진통제는비선택적소염진통제 (non-selective NSAID) 와 COX-2 선택적소염진통제 (COX-2 selective NSAID) 로구분한다. COX-1 과 COX-2 의기능이밝혀지면서비선택적소염진통제라불리는대부분의소염진통제의위장관합병증은아마도생리작용을담당하고있는 COX-1 을억제하기때문이며소염진통제의치료효과는주로 COX-2 의억제때문이라는소위 COX-2 가설 이등장하게되었다 40). 이러한가설을바탕으로 celecoxib, rofecoxib, valdecoxib, etorocoxib, lumiracoxib 와같은 COX-2 선택적소염진통제들이개발되게되었다 8,30). Celecoxib 와 rofecoxib 는 1세대 COX-2 선택적소염진통제로서 1999 년시장에나오게되었으며이후에개발된것은 2세대약물로불리워진다. 모든 COX-2 선택적소염진통제는비선택적소염진통제와상응하는우수한소염진통효과를지니면서도위장관에보다나은안정성을보여골관절염이나류마치성관절염의증상을치료하고기타급성기통증을치료하는데사용되어왔다. 최근심혈관계안전성특히혈전성질환 ( 급성심근경색, 불안정성협십증, 급사, 중풍 ) 에대한이들 COX-2 선택적소염진통제에대한염려가증가하고있다 1,19,24,35). 이러한위험성으로인해 celecoxib 를제외한나머지 COX-2 선택적소염진통제들은시장에서퇴출되거나 FDA 에승인받지못하였다. 현재까지 FDA 에승인되어시장에나와있는 COX-2 선택적소염진통제는 celecoxib 가유일하다 (Table 1). COX-2 선택적소염진통제의약동학 Cyclooxygenase (COX) 라는효소는우리몸속에 COX-1 과 COX-2 의두개의아형으로존재한다 15,21). 그중 COX-1 은 보호작용 (house-keeping) 을맡은효소로서몸어디에나있으며혈소판에서는유일하게발견되는효소로다양한생리적인반응을매개하며위장관점막, 신혈류역학 (hemodynamic) 및혈소판응집과정 47) 에중요하다. 반대로 COX-2 는주로염증과관계되는세포 ( 대식세포, 단핵세포, 활액막세포 ) 에서높게발현되며세균의지질다당류 (lipopolysaccharides), 사이토카인, 성장인자그리고종양인자 (tumor promotor) 에의해표현이증가된다. 하지만몇몇조직 ( 척수, 뇌, 신장, 혈관내피 ) 에서는 COX-2 또한생리적상황에서도지속적으로 (constitutively) Table 1. Classification and Basic Difference of COX-2 Selective NSAIDs Classification Drug Selectivity 39) (COX-2/COX-1) Chemical structure Market status 1st generation 2nd generation Celecoxib Rofecoxib Valdecoxib Etoricoxib Lumiracoxib Sulfonamide Sulfone Sulfonamide Sulfone Phenylacetic acid derivative Available Withdrawn in 2004 Withdrawn in 2005 Not approved by the FDA Not approved by the FDA Fig. 1. Regulation of prostaglandin biosynthesis by COX 41).

3 86 표현이되며 10) COX-1 또한염증이있으면어느정도의표현이증가될수있다 38). 이론적으로 COX-2 를선택적으로억제하면위장관점막의세포보호및혈소판기능을억제하지않으면서항염작용을나타낼수있을것이다 (Fig. 1). 실제로 COX-2 선택적소염진통제들은위장관과관련된합병증의감소로인해시장에나오자마자강력한위치를차지하게되었지만혈전성질환 ( 급성심근경색, 불안정성협십증, 급사, 뇌졸중 ) 의위험성을증가시킬수도있다는사실이알려지면서 celecoxib 를제외한다른 COX-2 선택적소염진통제들은시장에서퇴출되거나 FDA 에승인받지못하였다 1,19,24,35). 혈전성질환의위험성을증가시키는이유를알기위해선우선 COX-2 선택적진통소염제가비선택적소염진통제및심장보호효과가있는아스피린과의약리학적작용기전의차이를비교하는것이필요하다 13). PGI2 는혈관내피세포의 COX-2 에의해만들어지며혈소판의응집을막고혈관을이완시키는역할을하는반면 TxA2 는혈소판의 COX-1 에의해만들어지며혈소판응집을촉진시키며혈관을수축시킨다. 비선택적소염진통제인아스피린은혈관내피세포의 COX-2 와혈소판의 COX-1 모두를억제하여 PGI2 및 TxA2 합성을모두감소시키지만, 저용량사용시에는혈관내피세포에대한 COX-2 억제는일과성으로약하게나타나며, 혈소판에서 COX-1 의억제는아세틸화에의한비가역적으로나타나게되어그결과응집은막고혈관은이완시키는효과로인해뇌졸중및심근경색증을예방하는데널리사용되고있다 13). 하지만 COX-2 선택적소염진통제는 COX-2 에대한높은특이성으로인해혈관내피세포의 COX-2 를상대적으로더억제하게되므로그결과 PGI2 의합성이감소되고따라서혈소판응집이촉진되고혈관이수축되는쪽으로생리학적균형이이동되게되는것이다 13). 심혈관계위험성은 COX-2 선택적소염진통제에서높은것으로보고되고있으나심혈관계에미치는혈전성질환의위험도는 COX-2 선택적소염진통제의선택성 (selectivity) 정도에따라차이가있으며비선택적소염진통제 ( 예를들어 diclofenac,etodolac 등등 ) 들또한어느정도의 COX-2 선택성을가지고있다는사실에주목할필요가있다 (Fig. 2). 골관절염치료에서소염진통제의위장관계안전성비선택적소염진통제의사용과관련된가장큰문제는위장관에미치는다양한합병증즉무증상의위점막손상, 속쓰림, 소화불량부터생명을위협하는위출혈이나십이지장의궤양과관련이있다. 1주간의짧은복용에도위장관계합병증은발생할수있으며, 수개월간비선택적소염진통제복용시위장관계합병증의발생빈도는소화불량이 20%, 위십이지장궤양이 5%, 궤양의합병증즉위장관천공이나출혈이 0.25% 에달하며용량이증가할수록그위험도는더커진다 32). 특히전통적인궤양성질환과달리통증이적으면서도궤양의합병증즉위장관천공이나출 Table 2. Classical and NSAID-Induced Ulcers 36) Classical ulcer NSAID-ulcer Fig. 2. The spectrum of selectivity for cyclooxygenase (COX) inhibition 11,31). The drug concentrations required to inhibit COX-1 and COX-2 by 50% (IC50) have been measured using human whole blood assays of COX-1 and COX-2 activity in vitro. The line indicates equivalent COX-1 and COX-2 inhibition. Drugs plotted below the line are more potent inhibitors of COX-2 than drugs plotted above this line. The distance to the line is a measure of selectivity. Etiology H. pylori Favored Localization Frequency Symptoms Age Prognosis Multifactorial +++ Duodenum Mostly solitary Fasting pain < 60 years Low risk NSAID? Stomach Often multiple 40% without pain > 60 years High risk of perforation and bleeding

4 송영준ㆍ하철원 : 골관절염의치료에서 COX-2 선택적비스테로이드성소염진통제의이용 87 Table 3. Risk Factors for the Development of a NSAID- Gastropathy 36) Senior age (>60 years) Ulcer history within the last 5 years H. pylori infection High dosing and long duration of NSAID therapy Combinations of different NSAID Simultaneous glucocorticoid therapy Combination with low-dose aspirin Co-medication with anticoagulants Serious comorbidity Stress Alcoholism 혈의위험도가높다는것이비선택적소염진통제사용과관련된궤양의특징이다 37) (Table 2). 이러한비선택적소염진통제의위장관계합병증을피하기위해선위험인자를알고미리예방하는것이중요하다 (Table 3). 특히 H. pylori 감염의경우소염진통제와별도로위험도를높이기때문에 H. pylori 감염률이높은우리나라사람들에게서더욱주의를요한다. 예방을위해선비선택적소염진통제의용량을줄이거나, 프로톤펌프억제제 (proton pump inhibitor) 를함께복용하거나 COX-2 선택적소염진통제를사용하면된다. 참고로비선택적소염진통제의서방형 (delayed release preparation) 혹은장용제 (enteric coated tablet) 와같은것은위에서약제들의방출이적기때문에소화불량을줄일순있지만위장관궤양은막지못하는데, 이는궤양과관련된비선택적소염진통제의영향은위장관속에서방출된약물에의한것이아니라혈중에흡수된약물성분에의한것이기때문이다. COX-2 선택적소염진통제의안전성과관련된가장큰특징은비선택적소염진통제와비교하여위장관계합병증의발생빈도를크게낮춘다는점이다 5,17,25,32,33). COX-2 선택적소염진통제의위장관계합병증발생빈도를낮춘다는최초의대규모연구는 Vioxx Gastrointestinal Outcome Research (VIGOR) 이다. 이연구에서 Rofecoxib 군의위장관계합병증의발생빈도는 naproxen 군에비해절반이하로나타났다 (p<0.001) 5). Celecoxib Long-term Arthritis Safety Study (CLASS) 는관절염환자의치료를위해 celecoxib 와비선택적소염진통제 (diclofenac and ibuprofen) 의장기복용시상부위장관궤양및합병증의발생빈도를조사한연구로서 6개월치료후각각궤양 합병증발생률이 0.76% 대 1.45% (p=0.09), 증상을동반한궤양발생률이 2.08% 대 3.54% (p=0.02) 로나타났다. 하지만 aspirin 복용군을따로분석한결과에서는각각 2.01% 대 2.12% (p=0.92) 그리고 4.70% 대 6.00% (p=0.49) 로나타나아스피린복용군에서는유의한차이가없었다 32). 이에따라아스피린을복용하는환자에게있어 celecoxib 의위장관보호효과에대한정확한답을알기위하여 SUccessive Celecoxib Efficacy and Safety Study-1 (SUCCESS-1) 연구가이루어졌는데저용량의아스피린을복용중인골관절염환자를대상으로관절염환자의치료를위해 celecoxib 복용군 (100 또는 200 mg 을하루두번복용 ) 과비선택적소염진통제복용군 (diclofenac 50 mg 하루에두번혹은 naproxen 500 mg 하루두번복용 ) 의 12주치료후상부위장관궤양및합병증의발생빈도를조사한결과각각궤양합병증발생률이 0.8% 대 1.6% (p=1.00), 증상을동반한궤양발생률이 2.4% 대 6.6% (p=0.23) 로나타나전체적인수에서는 celecoxib 복용군에서상부위장관합병증의낮은유병률을보였지만통계학적인차이는없었다 33). 아스피린복용과관련된 celecoxib 의대규모역학조사에서위장관계합병증과관련된비선택적소염진통제의입원율을 1로보았을때 celecoxib 군은위험비율 (hazard ratio) 이 0.41 (95% confidence interval (CI) ) 로나타났으며 celecoxib 와아스피린을동시에복용하는군의위험비율은비선택적소염진통제와아스피린을동시에복용하는군과비교하였을때는위험비율이 0.62 (95% CI ) 로모두낮게나타났다 25). 특히비선택적소염진통제와연관된위장관계합병증병력이있는환자에서 celecoxib 의복용은비선택적소염진통제와프로톤펌프억제제를함께복용하는것에해당하는위장관보호효과를보인다고알려져있다 9,16). 따라서위장관합병증의위험인자를가지고있는환자에서소염진통제의복용특히관절염의급성기에진통작용과관절증상완화를위해소염작용이필요한경우에는비선택적소염진통제의경우프로톤펌프억제제를함께복용하거나 COX-2 선택적소염진통제를복용하는것이안전하겠다. 물론위험인자여부와관계없이 COX-2 선택적소염진통제를 6개월이상장기복용이필요할때에는프로톤펌프억제제와함께복용토록해야하며특히최근에궤양출혈병력이있거나여러위험인자를가진환자에게서는프로톤펌프억제제의복용이반드시필요하다.

5 88 골관절염치료에서소염진통제의심혈관계안전성위에서도기술했듯이 COX-2 선택적소염진통제는 TxA2 와 PGI2 의불균형을만들기때문에혈전성질환 ( 급성심근경색, 불안정성협심증, 급사, 중풍 ) 의위험을높일수있다. COX-2 선택적소염진통제의혈전성질환의위험이처음보고된것은 VIGOR 연구이며 rofecoxib 군에서 naproxen 군에비해혈전성질환 ( 주로급성심근경색 ) 이발생이 5배높게나타났으며 Adenomatous Polyp Prevention on Vioxx (APPROVe) study 에서다시한번혈전성질환의위험도가확인되어결국 rofecoxib 는시장에서퇴출되게되었다 5,7). 하지만 Celecoxib 의경우많은연구에서 celecoxib 는심혈관계위험을증가시키지않는다고보고되고있다 2,18,32,34,44). CLASS 연구에서 celecoxib 과비선택적소염진통제 (ibuprofen 과 diclofenac) 사이에서혈전성질환의유병률에있어차이를보이지않았으며, Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) 연구에서는위약 (placebo) 군과비교해서도혈전성질환의유병률에있어차이를보이지않았다 2,32). 울혈성심부전발생과관련하여입원율을조사한대규모역학조사에서도 celecoxib 는비선택적소염진통제복용군에비해증가하지않았으며 18) 급성심근경색의환자- 대조군연구에서도 celecoxib 는아무것도복용하지않는군, ibuprofen 군, naproxen 군과비교해서어떠한군과의비교에서도상대위험이증가하지않았다 34). 그러나이러한연구들이 celecoxib 의심혈관질환에대한안전성을보장하는것은아니며하루에 400 mg celecoxib 복용시에는심혈관계위험이증가한다는보고 4) 도있어주의를요하고있다. 최근미국 FDA 의표시제도 (labeling) 표기권장사항은 celecoxib 을포함한다른모든비선택적소염진통제복용시복용하지않은경우에비해심혈관계합병증의위험성이증가될수있음을표기하도록하고있다. 골관절염치료에서소염진통제의신장계안전성 COX-2 는신장에서지속성 (constitutively) 으로표현되며 이것은혈관내용적의변화에의해조절되며 10), COX-2 억제는일시적으로소변으로의 sodium 의배설을감소시켜혈압의상승을유도할수도있다 6,29). 신독성과관련하여 COX-2 선택적소염진통제는비선택적소염진통제와비슷하며신기능부전 (renal insufficiency), sodium 저류에따른고혈압, 말초부종 (peripheral edema), 고칼륨혈증및신유두괴사 (papillary necrosis) 를야기할수있다. 골관절염의치료에서 COX-2 선택적소염진통제의임상적이용증상을동반한골관절염환자의치료에있어일차약제로쓰이는아세트아미노펜 (acetaminophen) 에반응이없을때특히관절염의급성기에는소염작용을통한관절증상의완화를위해소염진통제의사용이필수적이다. 소염진통제를처방할때에는환자의나이, 아스피린과같은이미복용중인다른약물, 위장관계및심혈관계상태및동반질환등을고려하여결정해야하며골관절염의환자들은대부분고령이며위장관합병증의위험인자를가지고있는경우가많아이에따른위장관계합병증의위험이높다는점에주의해야한다. COX-2 선택적소염진통제는현재위장관계합병증의위험인자를가지고있거나아스피린을복용하는환자의경우비교적안전하게사용할수있는경구치료약제이다. COX-2 선택적소염진통제의통증억제효과는비선택적소염진통제와비슷하다고알려져있으며슬관절과고관절의골관절염의치료에관한 COX-2 선택적소염진통제와비선택적소염진통제와의비교연구에서도 COX-2 선택적소염진통제는효능면에서 naproxen 및 diclofenac 등과비슷한임상결과를보고하고있다 3,32). 골관절염의치료약제선택에있어전통적으로비용, 효과및안전성등의이유로아세트아미노펜이일차약물로사용되고, 소염진통제는아세트아미노펜에반응없을때이차약물로사용하는것이일반적이다. 하지만최근슬관절과고관절의골관절염환자를대상으로 Patient Preference for Placebo, Acetaminophen or Celecoxib Efficacy Studies (PACES) 연구에서는 celecoxib가 acetaminophen에비해부작용은통계학적으로차이가없으면서 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue pain scale, 환자선호도에서보다나은결

6 송영준ㆍ하철원 : 골관절염의치료에서 COX-2 선택적비스테로이드성소염진통제의이용 89 과를보이면서 celecoxib 를일차약물로권장하기도하였다 23). 최근대한슬관절학회에서전국의관절염환자 2,105 명을대상으로소염진통제를처방받는한국환자들이위장관계질환위험요인을얼마나가지고있는지를 SCORE 계산식 12) 에근거하여조사한결과, 약 51% 환자에서고위험군에해당하는위험인자를가지고있는것으로확인되었다. 이들고위험군의약 54% 에서는위장관계안전성이비교적우수한 COX-2 선택적소염진통제를처방받아복용중이었으나나머지 46% 에해당하는고위험군특히아스피린복용환자의 40%, 65세이상환자 43%, 위장관계합병증으로입원병력이있는환자 41%, 스테로이드복용환자 65%, 항응고제복용환자 35% 에서비선택적소염진통제를복용중인것으로확인되었다. 그러므로위장관계합병증예방을위해서관절염환자에게소염진통제처방시위장관계합병증관련위험요인이있는지여부를확인하는것이꼭필요할것으로생각되며, 또한약을처방받는환자들에게도이러한사항에대한홍보가필요하다고생각된다. 골관절염의수술적치료시의통증관리에서 COX-2 선택적소염진통제의임상적이용과거 COX-2 선택적소염진통제의역할은만성통증치료에초점이맞추어지면서이에따른장기복용에따른합병증여부가중요하였지만, 급성통증의치료에도그효능이밝혀지면서 COX-2 선택적소염진통제의역할도급성통증및술후통증관리에까지확대되었다 20,22). 최근에는통증기전에대한이해와함께통증관리에대한근본이론체계가변하면서수술후통증관리에있어서전위적통증관리와다면적통증관리라는새로운개념이등장하게되면서 COX-2 선택적소염진통제의역할이매우중요해지고있다. 전위적통증관리 (preemptive analgesia) 는통증이있기전에통증관리를한다는개념으로이의이론적배경은바로염증물질에의한중추와말초의감작 (central and peripheral sensitization) 이일어나면통증의악화및비정상적인통증이유발된다는데있다 46). 사실이러한개념은 50년전에이미등장하였으나비선택적소염진통제가수술후에미치는부작용때문에주목받지못하다가 COX-2 선택적소염진통제가개발되면서다시주목받기시작하게되었다. 수술과관련된통증은수술후정상적으로통증을일으키지않는자극에도통증이유발되며작은통증자극에비해매우커다란통증이발생이되는특징을가지고있으며이는염증물질이통증에대한역치를낮추기때문이다. 따라서수술후이러한염증물질에의한영향을차단하고자하는것이전위적통증관리이며이에효과적인약물이바로소염진통제이다. 여러연구에서수술직전에 COX-2 선택적소염진통제의투여가술후통증악화 (algesic flare) 를막는데효과적이며마약의사용양을줄여이에따른부작용을줄이는데도움이되며출혈양에있어서도차이가없다고보고하고있어수술전후통증조절에 COX-2 선택적소염진통제는매우유용하다고생각된다 26,27). 다면적통증관리 (multimodal analgesia) 는통증관리에있어두개이상의약제를이용하여약제들간의균형을통해부작용은줄이면서최적의통증조절은한다는것이다. 다면적통증관리측면에서소염진통제와마약성진통제, 국소마취제등이동시에사용될수있으며 ketamine 과같은 NMDA- 수용체길항제등도중추성감작 (central sensitization) 을줄이기위해사용될수있다. 비선택적소염진통제의경우혈소판및위장관에영향을미치므로수술부위의출혈및혈종발생과함께위장관궤양의발생을증가시키는문제점을가지고있어수술과관련하여사용에제한이있으나 COX-2 선택적소염진통제의경우이러한영향이적기때문에수술후에도안전하게사용이가능하다 26,28). Huang YM 등은전향적무작위적연구를통해슬관절전치환술을받는환자들을두군으로나누어자가통증조절장치 (patient controlled analgesics) 만으로술후통증조절하는군과자가통증조절장치와함께 celecoxib를수술한시간전에 400 mg 을투여하고수술후 5일동안 celecoxib 200 mg 을 12시간간격으로투여하는군을비교하였다. 그결과 celecoxib 를투여한군에서는그렇지않은군에비해마약성진통제의요구량이 40% 정도감소 (p=0.03) 하였으며통계학적으로유의하진않았지만마약성진통제의부작용인오심과구토증상도 15% 정도감소하였다. COX-2 선택적소염진통제와아세트아미노펜의상호상승효과 (synergic effect) 도보고되고있어 14) COX-2 선택적소염진통제가앞으로술후통증관리에더욱도움이될것으로기대된다.

7 90 요약및결론 소염진통제는항염작용, 진통작용, 그리고해열작용으로인하여골관절염환자의치료에서급성통증및만성염증관리를위해널리사용되고있다. COX-1 과 COX-2 효소억제의선택성에따라비선택적소염진통제와 COX-2 선택적소염진통제로구분되며, 소염및진통효과는비슷하나부작용면에있어서는차이가있다. 비선택적소염진통제의경우위장관계에다양한합병증이발생할수있으며, COX-2 선택적소염진통제는비선택적소염진통제와비교하여위장관계합병증을줄이는장점이있다. 심혈관계위험성은 COX-2 선택적소염진통제에서높은것으로보고되고있으나 COX-2 선택적소염진통제의선택성정도에따라차이가있다. 골관절염의급성기에는소염작용을통한관절증상완화를위해소염진통제의사용이필수적이며, COX-2 선택적소염진통제의경우혈소판에미치는영향이적어수술을앞둔골관절염환자의수술전후통증조절에유용하게사용될수있다. 소염진통제를처방할때에는환자의나이, 아스피린과같은이미복용중인다른약물, 위장관계및심혈관계상태및동반질환등을고려하여처방한다면, 골관절염환자의치료에서유용하면서안전하게사용될수있다. REFERENCES 1. Araujo LF, Soeiro Ade M, Fernandes Jde L, Serrano Júnior CV: Cardiovascular events: a class effect by COX-2 inhibitors. Arq Bras Cardiol, 85: , Arber N, Eagle CJ, Spicak J, et al: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med, 355: , Bensen WG, Fiechtner JJ, McMillen JI, et al: Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc, 74: , Bertagnolli MM, Eagle CJ, Zauber AG, et al: Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med, 355: , Bombardier C, Laine L, Reicin A, et al: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med, 343: , Brater DC, Harris C, Redfern JS, Gertz BJ: Renal effects of COX-2-selective inhibitors. Am J Nephrol, 21: 1-15, Bresalier RS, Sandler RS, Quan H, et al: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med, 352: , Capone ML, Tacconelli S, Di Francesco L, Sacchetti A, Sciulli MG, Patrignani P: Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat, 82: 85-94, Chan FK, Hung LC, Suen BY, et al: Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial. Gastroenterology, 127: , de Leval X, Hanson J, David JL, Masereel B, Pirotte B, Dogné JM: New developments on thromboxane and prostacyclin modulators part II: prostacyclin modulators. Curr Med Chem, 11: , FitzGerald GA, Patrono C: The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med, 345: , Fries JF, Williams CA, Bloch DA, Michel BA: Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med, 91: , Hinz B, Brune K: Cyclooxygenase years later. J Pharmacol Exp Ther, 300: , Issioui T, Klein KW, White PF, et al: The efficacy of premedication with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery. Anesth Analg, 94: , Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR: TIS10, a phorbol ester tumor promoter-inducible mrna from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem, 266: , Lai KC, Chu KM, Hui WM, et al: Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Am J Med, 118: , Laine L, Curtis SP, Cryer B, et al: Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid

8 송영준ㆍ하철원 : 골관절염의치료에서 COX-2 선택적비스테로이드성소염진통제의이용 91 arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet, 369: , Mamdani M, Juurlink DN, Lee DS, et al: Cyclo-oxygenase-2 inhibitors versus non-selective nonsteroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet, 363: , Maxwell SR, Webb DJ: COX-2 selective inhibitorsimportant lessons learned. Lancet, 365: , Nikanne E, Kokki H, Salo J, Linna TJ: Celecoxib and ketoprofen for pain management during tonsillectomy: a placebo-controlled clinical trial. Otolaryngol Head Neck Surg, 132: , O'Banion MK, Sadowski HB, Winn V, Young DA: A serum- and glucocorticoid-regulated 4-kilobase mrna encodes a cyclooxygenase-related protein. J Biol Chem, 266: , Petrella R, Ekman EF, Schuller R, Fort JG: Efficacy of celecoxib, a COX-2-specific inhibitor, and naproxen in the management of acute ankle sprain: results of a double-blind, randomized controlled trial. Clin J Sport Med, 14: , Pincus T, Koch G, Lei H, et al: Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis, 63: , Psaty BM, Furberg CD: COX-2 inhibitors--lessons in drug safety. N Engl J Med, 352: , Rahme E, Bardou M, Dasgupta K, Toubouti Y, Ghosn J, Barkun AN: Hospitalization for gastrointestinal bleeding associated with non-steroidal antiinflammatory drugs among elderly patients using lowdose aspirin: a retrospective cohort study. Rheumatology (Oxford), 46: , Reuben SS, Connelly NR: Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg, 91: , Reuben SS, Fingeroth R, Krushell R, Maciolek H: Evaluation of the safety and efficacy of the perioperative administration of rofecoxib for total knee arthroplasty. J Arthroplasty, 17: 26-31, Robinson CM, Christie J, Malcolm-Smith N: Nonsteroidal antiinflammatory drugs, perioperative blood loss, and transfusion requirements in elective hip arthroplasty. J Arthroplasty, 8: , Schwartz JI, Vandormael K, Malice MP, et al: Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normalsalt diet. Clin Pharmacol Ther, 72: 50-61, Seibert K, Masferrer J, Zhang Y, et al: Mediation of inflammation by cyclooxygenase-2. Agents Actions Suppl, 46: 41-50, Shi S, Klotz U: Clinical use and pharmacological properties of selective COX-2 inhibitors. Eur J Clin Pharmacol, 64: , Silverstein FE, Faich G, Goldstein JL, et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. Jama, 284: , Singh G, Fort JG, Goldstein JL, et al: Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med, 119: , Solomon DH, Schneeweiss S, Glynn RJ, et al: Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation, 109: , Sooriakumaran P: COX-2 inhibitors and the heart: are all coxibs the same? Postgrad Med J, 82: , Steinmeyer J, Konttinen YT: Oral treatment options for degenerative joint disease--presence and future. Adv Drug Deliv Rev, 58: , Straus WL, Ofman JJ, MacLean C, et al: Do NSAIDs cause dyspepsia? A meta-analysis evaluating alternative dyspepsia definitions. Am J Gastroenterol, 97: , Taniura S, Kamitani H, Watanabe T, Eling TE: Transcriptional regulation of cyclooxygenase-1 by histone deacetylase inhibitors in normal human astrocyte cells. J Biol Chem, 277: , Topol EJ, Falk GW: A coxib a day won't keep the doctor away. Lancet, 364: , Trevethick MA, Oakley I, Clayton NM, Strong P: Non-steroidal anti-inflammatory drug-induced gastric damage in experimental animals: underlying pathological mechanisms. Gen Pharmacol, 26: , 1995.

9 Vane J: Towards a better aspirin. Nature, 367: , Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol, 231: , Wallace JL: Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology, 112: , White WB, Faich G, Borer JS, Makuch RW: Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol, 92: , Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med, 340: , Woolf CJ, Chong MS: Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg, 77: , Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL: Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mrna splicing. Proc Natl Acad Sci U S A, 88: , = 국문초록 = 비스테로이드성소염진통제 (Nonsteroidal anti-inflammatory drug; NSAID; 이하소염진통제 ) 는항염작용, 진통작용, 그리고해열작용을가진약물로서급성통증및만성염증관리를위해광범위하게사용되고있다. 소염진통제의작용기전은프로스타글란딘 (prostaglandin) 의생성억제이며프로스타글란딘은주로생리작용을담당하는 COX-1 과염증반응을매개하고있는 COX-2 효소에서생성되는데, 이들효소의선택성에따라소염진통제는비선택적소염진통제 (non-selective NSAID) 와 COX-2 선택적소염진통제 (COX-2 selective NSAID) 로구분한다. 비선택적소염진통제와 COX-2 선택적소염진통제의소염및진통효과는비슷하나, 비선택적소염진통제의사용과관련된가장큰문제는 COX-1 에억제에따른위장관계에미치는다양한합병증이며, COX-2 선택적소염진통제는비선택적소염진통제와비교하여위장관계합병증을줄이는장점이있다. 심혈관계위험성은 COX-2 선택적소염진통제에서높은것으로보고되고있으나 COX-2 선택적소염진통제의선택성정도에따라차이가있다. 골관절염의급성기에는소염작용을통한관절증상완화를위해소염진통제의사용이필수적이나, 소염진통제를처방할때에는환자의나이, 아스피린과같은이미복용중인다른약물, 위장관계및심혈관계상태및동반질환등을고려하여결정해야한다. COX-2 선택적소염진통제의경우혈소판에미치는영향이적어수술을앞둔골관절염환자의수술전후통증조절을위해서도유용하게사용될수있다. 색인단어 : 소염진통제, COX-2 선택적, 골관절염, 치료

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract