경구용 트롬빈 억제제, LB30057의 돼지의 관동맥 손상모델에서 재협착에 미치는 영향 = LB30057, a Direct Thrombin Inhibitor, the Effect of Restenosis in Porcine Coronary Injury Model

다국어 초록 (Multilingual Abstract)

Background and Objectives ：In a previous study, LB3057 was found to inhibit smooth muscle cel proliferation in a dose dependent maner, and prolonged 14-day oral administration of LB30057 is effective in reducing the neointimal hyper -plasia in a rat carotid balloon injury model. The prolonged administration of LB30057, an orally active direct thrombin inhibitor, was evaluated and found to be a potential inhibitor of restenosis in a porcine coronary injury model. Materials and Methods ：An oversized ballon injury and a stent injury were given to the right coronary artery and left anterior descending artery, respectively, in the porcine model. LB30057 (50 mg/kg) or a placebo was administrated for 28 days, antithrombotic efects (aPT, thrombin-anti thrombin complex levels) were measured, and a histo -morphometric analysis performed 28 days later. Results：The drug concentrations were 27 1± 124 and 67 ± 52 ng/mL on days 1 and 28 after injury in the drug group. The TAT (thrombin -antithrombin complex) levels were significantly lower in the drug than the control group on the 2nd and 7thluminal, intimal and medial areas betwen the two groups. Conclusion ：Prolonged administration of LB3057, using an osmotic pump, was not effective in reducing the restenosis in our pig coronary injury model.

국문 초록 (Abstract)

배경 및 목적： 이전 연구에서 경구용으로 개발된 트롬빈 저해제인 LB -30057의 실험실내에서 혈관 평활 근 세포의 증식억제 효과와 흰쥐의 경동맥 손상 모델에서 신내막 증식에 대한 효과를 검증하여 보고 하였다. 이에 본 연구는 큰 동물인 돼지의 관동맥 손상 모델에서 본 약제의 관동맥 재협착에 미치는 영향을 보고자 하였다. 방 법： 약제의 재협착 효과를 검증하기 위해 돼지의 관상동맥 모델을 이용하였고 혈관 조영술 하에 좌전 하행지에는 풍선 손상을 우 관동맥에는 스텐트를 삽입하였다. 약물 투여 군 및 대조 군에 osmotic pump(ALZET, ALZA corp., USA)를 부착시켜 손상 6시간 전부터 희생 시 까지 약제를 투여 하였다. 약제 농도 및 항 응고 효과를 확인 하기 위해 시간대별로 aPT, TAT(thrombin antithrombin Ⅲ complex), 약제 농도를 측정하였고, 28일 후 돼지를 희생시켜 관동맥을 분리 하였고 조직 병리학적인 특징을 관찰하였다. 결 과：혈중 내 LB30057의 농도 변화는 대조군에서 시술 후 1일째 소량의 농도가 검출되었으나 이후로는 약제가 검출되
Byung-Su Yoo, et al：LB30057, A Direct Thrombin Inhibitor, the Effect of Restenosis·21
지 않았고 약제 투여 군에서 혈중 내 LB30057의 변화 추이는 시술 후 1일째 가장 높은 농도(271±124 ng/mL)로 유지되다가 28일 후에는 67±52 ng/mL로 감소되었다. 또 한 TAT 시간대별 차이는 두 군간에 유의한 차이가 없었으나 2일(33.62±14.34 vs. 20.24±10.34 ng/mL, p<0.05)과 7일(31.87±12.36 vs. 7.98±6.21 ng/mL, p<0.05)에 는 약제 투여 군에서 유의하게 낮았다(p<0.05). 돼지의 관상동맥에 풍선 손상 모델 및 스텐트 삽입의 손상의 정도 및 손상 후 조직 형태학적 차이는 양군간에 유의한 차이가 관찰되지 않았다. 결 론：본 연구에서 경구용 트롬빈 억제제인 LB30057의 투여는 돼지의 관동맥 손상 모델에서 유의한 신내막 증식 억제 효과를 나타내지 못하였다.

참고문헌 (Reference)

• 1 "is an effective antithrombotic agent in rodent models ofarterial and venous thrombosis comparisons with heparin" wi i (wi i): 431-2763 8, thrombhaemost1998
• 2 "Thrombin stimulatesvascular smooth muscle cell polyamine synthesis by inducingcationic amino acid transporter and ornithine decarboxylase geneexpression" 83 : 217-23, 1998
• 3 "The role of platelets,thrombin and hyperplasia in restenosis aftercoronary angioplasty" 17 : 1991
• 4 "The porcine coronarymodel of in-stent restenosis:current status in the era ofdrug-eluting stents" 60 : 515-23, 2003
• 5 "Structural modification of anorally active thrombin inhibitor replacement of theD-pocket-binding naphthyl moiety" 6 : 869-76,
• 6 "Role of the thrombinreceptor in restenosis and atherosclerosis" 75 : 828-7B, 1995
• 7 "Restenosis and theproportional neointimal response to coronary artery injury:resultsin a porcine model" 19 : 267-74, 1992
• 8 "Restenosis after successfulpercutaneous transluminal coronary angioplasty:serialangiographic follow-up of 229 patients" 12 : 616-23, 1988
• 9 "Restenosis after successfulcoronary angioplasty:pathophysiology and prevention" 318 : 1734-7, 1988
• 10 "Prolonged thrombin inhibitionreduces restenosis after balloon angioplasty in porcine coronaryarteries" 97 : 581-8, 1998
• 11 "Probucol decreasesneointimal formation in a swine model of coronary artery ballooninjury:a possible role for antioxidants in restenosis" 88 : 628-37, 1993
• 12 "Plateletaggregation induced in vitro by rabbit plasma clot-associatedthrombin,and its inhibition by thrombin inhibitors" 80 : 840-4, Haemost1998
• 13 "Melagatron,an oral active-site inhibitor of thrombin,prevents or delays formation of electrically induced occlusivethrombus in the canine coronary artery" 31 : 345-51, Pharmacol1998
• 14 "Measurement of solublefibrin monomerfibrinogen complex in plasmas derivedfrom patients with various underlying clinical situations" 89,89 : 832 ,832-6 ,6, thrombhaemost2003haemost2003
• 15 "LB30057,a directthrombin inhibitor,inhibits vascular smooth muscle cell proliferationin vitro and the neointimal hyperplasia in rat carotid injurymodel" 31 : 909-17, 2001
• 16 "Discovery of LB30057,a benzamidrazone-based selective oral thrombin inhibitor" 8 : 631-4, 1998
• 17 "Comparison of sustained antithrombotic effects of inhibitors ofthrombin and factor Xa in experimental thrombosis" 93 : 153-60, 1996
• 18 "Comparative safety profiles of hirulog and heparin inpatients undergoing coronary angioplasty" 130 : 658-65, 1995
• 19 "Arterial thrombinactivity after angioplasty in an atherosclerotic rabbit model:timecourse and effect of hirudin" 94 : 88-93, 1996
• 20 "Arterial injury and the enigma of coronaryrestenosis" 19 : 275-7, 1992
• 21 "Antithrombotic effects of hirulog in a rat carotid endarterectomymodel" 60 : 15-22, 1996
• 22 "Antithrombin III inhibits thrombin-induced proliferation in humanarterial smooth muscle cells" 14 : 254-60, 1994
• 23 "A comparison of hirudinwith heparin in the prevention of restenosis after coronary angioplasty" 333 : 757-63, 1995