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1 대한내과학회지 : 제 86 권제 2 호 만성간질환에서펜넬 R 의무작위, 이중맹검, 다기관제4상임상시험 1 중앙대학교의과대학내과학교실, 2 인제대학교의과대학내과학교실, 3 연세대학교원주의과대학내과학교실, 4 가톨릭대학교의과대학내과학교실, 5 한양대학교의과대학내과학교실, 6 한림대학교의과대학내과학교실, 7 차의과대학교내과학교실 김형준 1 이준성 2 이현웅 1 김문영 3 남순우 4 손주현 5 조세현 4 윤승규 4 양진모 4 박충기 6 임규성 7 이영석 4 The PERFECT Study (PEnnel Real life Efficacy Clinical Trial), a Double-Blind, Randomized, Multicenter Trial Examining the Efficacy of Biphenyl Dimethyl Dicarboxylate Combined with Garlic Oil in Patients with Transaminase Elevated Chronic Liver Disease Hyung Joon Kim 1, June Sung Lee 2, Hyun Woong Lee 1, Mun Young Kim 3, Soon Woo Nam 4, Ju Hyun Sohn 5, Se Hyun Cho 4, Seung Gyu Yoon 4, Jin Mo Yang 4, Chung Kee Park 6, Gyu Sung Rim 7, and Young Sok Lee 4 1 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul; 2 Department of Internal Medicine, Inje University College of Medicine, Busan; 3 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju; 4 Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul; 5 Department of Internal Medicine, Hanyang University College of Medicine, Seoul; 6 Department of Internal Medicine, Hallym University College of Medicine, Chuncheon; 7 Department of Internal Medicine, CHA University, Seoul, Korea Background/Aims: Biphenyl dimethyl dicarboxylate (DDB) combined with garlic oil (pennel) has been used to treat chronic liver disease. A randomized, double-blind, active- and placebo-controlled clinical trial was conducted to investigate the efficacy, safety and quality of life in chronic liver disease patients. Methods: A total of 237 patients with chronic liver disease were randomized into three groups; 100 patients were administered pennel, 102 patients Legalon as an active-control and 35 patients placebo for 12 weeks. The primary endpoint was the rate of alanine aminotransferase (ALT) normalization. We assessed differences in ALT levels and malondialdehyde (MDA) as an oxidative biomarker between 0 and 12 weeks, the improvement in quality of life using a chronic liver disease questionnaire (CLDQ) and the incidence of adverse events. Received: Revised: Accepted: Correspondence to Young Sok Lee, M.D. Ph.D. Department of Internal Medicine, The Catholic University of Korea Bucheon St. Mary's Hospital, 327 Sosa-ro, Wonmi-gu, Bucheon , Korea Tel: , Fax: , yslee525@gmail.com * This study was supported by PharmaKing Company. Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 - The Korean Journal of Medicine: Vol. 86, No. 2, Results: Among 237 patients, there were 157 patients with non-alcoholic fatty liver disease, 36 patients with alcoholic liver disease, and 28 patients with chronic hepatitis B and C. The incidence of ALT normalization at 12 weeks was 89% for the pennel group, 18.6% for the active-control group, and 22.9% for the placebo-control group (p < 0.001). The difference in serum ALT level between 0 and 12 weeks was significantly higher in the pennel group (p < 0.001) and the level of MDA was decreased in the pennel group, statistically (p < 0.001). There was no difference in incidence of adverse events among groups. The pennel group showed significant improvement based on the CLDQ (p < 0.001). Conclusions: Pennel can effectively improve the rate of ALT normalization and the quality of life with a safety profile in chronic liver disease. (Korean J Med 2014;86: ) Keywords: Chronic liver disease; Biphenyl dimethyl dicarboxylate; Transaminase; Clinical trial 서론만성간질환은일반적으로원인과상관없이반복적인염증반응과치유과정이 6개월이상장기간지속되면간섬유화를거쳐서간경변증으로진행하는질환이다. 만성간질환의원인으로는 B형, C형간염바이러스, 알코올또는비알코올성지방간및여러가지약물이나간독성물질등이알려져있다. 따라서간경변증으로의이환예방및치료를위해원인의진단및치료가무엇보다도중요하다 [1,2]. 그러나항바이러스치료기준에합당하지않거나원인제거가어려울경우에주로아시아와일부서양국가들에서간질환의경과에도움이되는여러가지간보호제들이사용되고있고간세포보호를주목적으로하는 biphenyl dimethyl dicarboxylate (DDB), silymarin (Legalon ) 과 ursodeoxycholic acid (UDCA) 등의약제가만성간질환에대한보조적치료제로사용되어지고있으며약제간작용기전이서로달라종종병용투여를하고있다 [3-6]. 본연구의시험약제인펜넬 (Pennel ) 의주된성분인 DDB 는바이러스간염을포함한다양한원인의만성간질환환자대부분에서간기능을쉽게평가할수있는혈청 ALT를의미있게감소시키는것으로알려져있다. 하지만일부보고에따르면 DDB는간생검상조직학적인괴사염증지수나간섬유화에는영향을미치지않고생체외연구에서도간세포내에서 ALT의합성과분해에만영향을미치는것으로보고하였다 [7]. 본연구의시험약인펜넬 (Pennel ) 은 DDB에마늘유 (garlic oil) 를복합시킨제제로, DDB는 cytochrome P450B를증가시켜간세포의보호와치료효과를보이며또한마늘유에함유된유기황화합물 (allyl sulfide, allyl disulfide) 은싸이토크롬 P450E의활성과발현을억제하고 glutathione-s-transferase의활성을촉진함으로써간독성과암발생을억제한다고보고되고있다. 동물실험에서쿠퍼세포와사멸된간세포수의측정을통해서도 DDB가간보호역할을하는것으로보고하고있으며사염화탄소유발간손상인중심부괴사, 간세포퇴행및염증을보다효과적으로완화시킨다고알려져있다 [8,9]. 또한펜넬은만성바이러스간염환자들을대상으로한이중맹검, 위약대조, 임상연구에서혈청트랜스아미나제수치를의미있게감소시키며안전성이확인되었으나아직까지적정수의환자를대상으로한잘고안된무작위, 이중맹검, 전향적임상시험이없다. 또한혈청학적간염의지표로사용되는 ALT의변화와더불어항산화효과를확인할수있는지표에관련된연구가없다. 이에본연구는혈청트랜스아미나제가상승된만성간질환환자에서펜넬의치료효과에대한유효성을검증하기위해활성대조약인레가론, 위약대조군과비교평가한다기관제4상임상연구를실시하였다. 대상및방법대상피험자및피험자수국내 11개다기관에서무작위, 이중맹검, 평행군, 대조약및위약비교, 제4상임상시험으로선정 / 제외기준에적합한트랜스아미나제가상승된만성간질환환자를대상으로연구를진행하였다. 대상환자의선정기준은다음과같이 1) 만 20세이상의성인남녀, 2) 스크리닝기간중 ALT > 60 U/L 인환자, 3) 최소 3개월이상임상시험에참여하여 ALT 및 AST 를평가할수있는환자, 4) 다음중하나이상의소견이확
3 - Hyung Joon Kim, et al. The efficacy of pennel in chronic liver disease - 인되어만성간질환으로진단받은자, i) 임상시험참여 6개월이전, 혈청트랜스아미나제 (ALT or AST) 의 1회이상측정결과가이상소견, ii) 초음파검사상만성간질환또는지방간소견, iii) 30일이상간질환치료제를복용한만성간질환의치료력이있는자, 5) 임신반응검사 (urine) 에서음성으로확인되었으며가임기여성은임상시험기간동안피임에동의한경우였다. 제외기준은다음조건의어느하나라도해당되는경우로서 1) 특이적간질환자, i) 트랜스아미나제가정상인자가면역간염환자, ii) 항바이러스약물을투여중인바이러스간염환자 (B, C 형간염 ), iii) 유전성간질환자, 2) 스크리닝기간중 ALT > 10 UNL (upper normal limit) 인환자, 3) 복수, 식도정맥의출혈, 간성뇌병증의간경변환자, 4) 중증의질환자, i) 다기관부전 (multisystem failure), ii) 암 (cancer), iii) 조절되지않는당뇨병 (Hb A1C > 8%), 5) 신기능또는심장기능부전환자, 6) 중증또는잘조절되지않은정신과환자, 7) HIV 양성으로확인한자, 8) 장기이식또는골수이식을받은병력이있는경우, 9) 스크리닝방문전 30 일이내에스테로이드약물을 14일이상경구복용한적이있는경우, 10) 스크리닝방문전 2주이내만성간질환치료제 ( 예 : DDB, Silymarin, Vitamin 등 ) 를사용한적이있는경우 11) 스크리닝방문전 30일이내다른임상시험에참여한적이있는경우 12) 임상시험기간중알코올 ( 하루평균알코올남자 30 g/ 여자 15 g 이상음주 )/ 약물을통제할수없는경우 13) 본임상시험용의약품 ( 시험약및대조약 ) 에알러지반응의과거력을가진환자 14) 임신부또는수유부였다. 임상시험기간은 12주이었으며피험자수의산정은다음과같았다. 과거논문에서만성활동성간질환환자에게 DDB를 3개월투여했을때혈청 ALT가정상범위에속하게되는분율은 89.5% 라고보고하였다 [10]. 이에반해위약을투여한환자의 3개월후 ALT가정상범위에속하게되는분율은약 5% 였다. 본연구에서도투여 12주의정상화분율이 85% 가될것으로추정하였다. Buzzelli는본연구의활성대조약인레가론성분과동일한 silybin phytosome을만성간질환자에게일주일간의짧은기간동안투여했을때피험자의 29% 에서혈청 ALT가감소하였다고보고하였다 [11]. 따라서펜넬캡슐을사용하는시험약군과레가론을사용하는활성대조군의 12주후 ALT의정상화분율은같다고가정하였다. 피험자수는시험약군과활 성대조약군이 89명이필요하며, 중도탈락률 20% 를고려하였을때시험약군과활성대조약군각각 112명으로총 224명의환자를대상으로하였다. 본임상시험은연구에참여한각병원의임상심의위원회 (IRB) 의심사와승인을얻었으며피험자모두로부터서면동의를받았다. 연구방법연구설계활성대조약이본임상시험에서이전의효과가재현되지않을가능성으로인한오류를배제하고시험약의유효성을증명하기위하여위약군을설정하였다. 피험자는시험약군과활성대조군과위약군을 3:3:1로무작위배정하였으며기관별로블록무작위배정법으로배정하였다. 본연구의피험자등록은경쟁적등록으로진행하였다. 모든피험자는동의서서명을전제로하였으며무작위배정을하기전선정제외기준에적합한피험자만등록하였다. 무작위배정치료는시험약 ( 펜넬 ), 활성대조약 ( 레가론 ) 및위약에대하여이중맹검으로진행하였다. 연구선정등록기준을만족시키는총 237명의피험자가등록되었다. 시험약군은펜넬캡슐 (480 mg/capsule) 1회 2캡슐과대조약 ( 레가론 ) 위약 1회 1캡슐을, 활성대조군은대조약레가론 (339.4 mg/capsule) 1회 1캡슐과시험약 ( 펜넬 ) 위약 1회 2캡슐을, 위약대조군은시험약 ( 펜넬 ) 위약 (Lactose 480 mg/capsule) 1회 2캡슐과활성대조약 ( 레가론 ) 위약 (Lactose mg/capsule) 1회 1캡슐을하루세번투약받았으며투여기간은 84일이었다 (Fig. 1). 모든피험자는스크리닝방문일 ( 스크리닝 ; 방문1 전 2주이내 ) 을기준으로혈청트랜스아미나제검사를받았다. 방문 1 ( 치료약투약 1일 ), 방문 2 (4주 ± 5일 ), 방문 3 (8주 ± 5일 ), 방문 4 (12주 ± 5일 ) 마다공복상태에서생체징후검사, 이학적검사, 일반혈액검사, 혈청생화학검사, 지질검사, 및소변검사를하였다. 항산화검사는방문 1과 4에서만시행하였다. 방문 1에시행한혈청트랜스아미나제의수치를유효성측정변수기본값으로정하였다. 방문 1과 4에피험자에게 chronic liver disease questionnaire (CLDQ) 를이용한설문조사를하였다. CLDQ 는경증과중증만성간질환자에서증상및건강과관련된삶의질평가를측정하기위해개발된 29개항목으로서피험자가직접보고
4 - 대한내과학회지 : 제 86 권제 2 호통권제 642 호 하는설문조사이며 2주이상기간으로설계되어있으며조사항목은활동도 / 에너지, 정서, 전신증상, 걱정으로각항목은 1점-7점으로점수가높을수록상태가좋은것을의미한다. 치료전후피험자의삶의질을평가하기위하여만성간질환자의삶의질관련설문조사 (Chronic liver disease questionnaire) 를하였다. 안전성평가를위해임상시험기간동안방문시점마다이상반응의발생여부를확인하였다. 이상반응은임상시험용의약품과의인과관계와상관없이이상반응명, 이상반응의중증도, 발현날짜, 소실날짜, 임상시험용의약품과의연관성에관한시험자의의견, 중대한이상반응여부와이로인한중도탈락여부등을조사하였다. 일차연구목적은만성간질환자에서펜넬을투여하는시험군과레가론을투여하는활성대조군의투약 12주후의혈청 ALT 수치가정상화된환자의분율을비교하여비열등함을입증하는것이다. 만약시험약이활성대조약보다비열등하면시험약이활성대조약보다우월한지를평가하였다. 이차연구목적으로첫번째방문 ( 방문 1) 대비하여각군의투약후 12주의 ALT, AST, γ-gtp, ALP, Albumin 및 Total bilirubin 의변화량을, 각각비교하여시험약의임상적유효성을평가하고자하였으며만성간질환설문조사 CLDQ를사용하여시험약펜넬이증상및건강에관련된삶의질 (health related quality of life) 에미치는영향을평가하고자하였다 [12-13]. 또한펜넬이지질검사 (cholesterol, triglyceride), 항산화검사 (thiobarbituric acid reactive substances, TBARS; malondialdehyde, MDA) 에미치는영향을분석하였다. 통계분석피험자로부터얻어진기초자료중범주형자료의경우카이제곱검정 (chi-square test) 과 Fisher s exact test을이용하여비교하였으며연속형자료의경우 one-way ANOVA 와 Kruskal- Wallis test를이용하여비교, 분석하였다. 또한각군간의투약전혈청 ALT 대비치료시작후 12주의혈청 ALT 수치가정상화분율의차이는카이제곱검정 (chi-square test) 과 Fisher s exact test를이용하여비교하였다. 치료시작후 12주에서의각군간의간기능지표인자차이는 paired t-test, Wilcoxon's signed rank sum test를이용하여비교하였다. 만성간질환환자의삶의질관련평가설문을이용하여기저대비투약후 12주 ( 또는중도탈락시 ) 에서의 CLDQ (Chronic liver disease questionnaire) 총점수변화량및각변수의점수 변화량을 paired t-test, Wilcoxon's signed rank sum test와 Friedman test를이용하여비교하였다. 또한항산화효과를평가하기위해 TBARS 와 MDA의기저대비 12주의평균변화량을 Wilcoxon s signed rank sum test를이용하여비교하였다. 피험자의이상반응의빈도, 정도등과이학적검사, 일반혈액검사, 혈액화학검사, 요검사등의실험실적검사결과에서의이상소견을평가하였으며중증도별이상반응발생률은 chi-square test 혹은 Fisher s exact test를이용하여분석하였다. 피험자의이상반응의빈도, 정도등과이학적검사, 일반혈액검사, 혈액화학검사, 요검사등의실험실적검사결과에서의이상소견을평가하였으며중증도별이상반응발생률은 chi-square test 혹은 Fisher s exact test를이용하여분석하였다. 모든분석에서 p 값이 0.05 미만인경우를유의한것으로판단하였다. 대상 환자의특성 결 본연구에서는총 262명의환자가등록되었고 25명이피험자선정기준과부합되지않아제외되었으며 237명의피험자가연구에참여하였다. 이중시험약군은 100명, 활성대조군은 102명, 위약군은 35명이었다. 12주간의치료기간동안투약순응도는좋았으며중도탈락이나계획서위반사항은없었다 (Fig. 1). 환자의연령은세군간에유의한차이가없었으나성별 Figure 1. Clinical flow chart. A total of 262 patients had elevated alanine aminotransferase (ALT) and 25 were excluded based on the exclusion criteria. The clinical trial included 237 randomized patients. 과
5 - 김형준외 11 인. 만성간질환에서펜넬의임상효과 - Table 1. Baseline patient characteristics Characteristics Pennel (n = 100) Active control (n = 102) Placebo control (n= 35) Total (n = 237) p value a Male:Female (n) 78:22 72:30 19:16 169: Male:Female (%) (78:22) (70.6:29.4) (54.3:45.7) (71.3:28.7) Age (yr, range) 44 (20-79) 49 (20-75) 44 (24-77) 46 (20-79) AST (U/L, range) b 58.5 (24-288) 60.5 (15-391) 58 (27-243) 59 (15-391) ALT (U/L, range) b 90.5 (38-300) 88 (45-300) 92 (61-230) 91 (38-300) Total bilirubin (mg/dl, range) 0.8 ( ) 0.8 ( ) 0.7 ( ) 0.8 ( ) Albumin (g/dl, range) 4.6 ( ) 4.5 ( ) 4.6 ( ) 4.6 ( ) γ-gpt (U/L, range) 71 (13-696) 72 ( ) 65 (26-390) 70 ( ) ALP (U/L, range) 165 (45-638) 157 (45-449) 126 (46-336) 159 (45-638) Total cholesterol (mg/dl) ± ± ± ± Triglyceride (mg/dl) 156 (32-491) 140 (47-908) 145 (50-629) 145 (32-908) TBARS (nmol/ml, range) 9.1 ( ) 8.6 ( ) 9.9 ( ) 9.3 ( ) MDA (pmol/mg, range) 5.9 ( ) 6.0 ( ) 5.7 ( ) 6.0 ( ) Etiology HBV 6 (6.0) 9 (8.8) 1 (2.9) 16 (6.8) HCV 16 (16.0) 9 (8.8) 3 (8.6) 28 (11.8) NAFLD 65 (65.0) 65 (63.7) 27 (77.1) 157 (66.2) Alcohol 13 (13.0) 19 (18.7) 4 (11.4) 36 (15.2) Values are given as the median (range) or mean ± standard error of the mean. AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-gpt, gamma-glutamyl transferase; ALP, alkaline phosphatase; TBARS, thiobarbituric acid reactive substances; MDA, malondialdehyde; NAFLD, non-alcoholic fatty liver disease. a Chi-square test, Kruskal-Wallis test and one-way ANOVA test. b Upper limit of normal AST/ALT levels < 40 U/L. 에있어서모든군에서남성이많았으나특히시험약군과활성대조군에서남성의비율이높았다. 약물투약이전생화학적간기능검사를포함한일반혈액검사, 일반화학검사, 전해질검사, 지질검사및항산화검사소견에서세군간의유의한차이가없었으며간염의원인비율도차이가없었다. 전체환자의치료전평균 ALT는 90 U/L였으며 66% 가비알코올성지방간염, 15% 가알코올성간염, 약 12% 가만성 C형간염, 그리고 7% 가만성 B형간염환자였다 (Table 1). 혈청트랜스아미나제 (ALT) 수치의정상화분률평가약물투약 12주째 ALT 정상화분율은시험군이 89명 (89%), 활성대조군이 19명 (18.6%), 위약군이 8명 (22.9%) 이었다 (p < 0.001). 간염의원인에따른하위그룹분류에서도시험약군에서통계적으로의미있게 ALT 정상화분율이높았다 (Table 2). 치료전대비치료후 12주의 ALT는시험약군에서평균 85 U/L 감소하였으나활성대조군은 20 U/L 감소하였고위약군은 25 U/L 감소하였다. 치료 12주간 ALT 수치의 변화량도시험약군에서통계적으로의미있게높았다 (Fig. 2). 간염의원인에따른하위그룹분석에서도시험약군에서 ALT 수치가유의하게감소하였다. 혈청일반화학검사수치와항산화수치의변화량평가약물투약 12주째 AST 수치의변화량은시험군약에서평균 27 U/L, 활성대조군은 11 U/L, 위약군은 21 U/L 감소하였다. 시험약군에서 AST 수치가 4주, 8주에활성대조군, 위약군에비해통계적으로의미있게감소하였으나 12주에서는유의한차이를보이지않았다 (Fig. 3). 항산화수치의변화를 TBARS 와 MDA를이용하여측정하였다. TBARS 는치료전대비약물투약 12주의변화량이세군간유의한차이가관찰되지않았으나 MDA는시험약군에서는 1.4 pmol/mg의감소가관찰되었고활성대조군과위약군에서는감소가관찰되지않아통계적으로의미있는항산화수치의호전을보였다 (Fig. 4). 특히하위그룹분석에서본연구의대상환자빈도가높았던비알코올성지방
6 - The Korean Journal of Medicine: Vol. 86, No. 2, Table 2. The rate of ALT normalization based on hepatitis etiology Etiology Pennel Active control Placebo control Total p value a Viral hepatitis (n) ALT 40 U/L (%) 22 (100) 3 (16.7) 1 (25.0) 26 (59.1) < ALT > 40 U/L (%) 0 (0) 15 (83.3) 3 (75.0) 18 (40.9) NAFLD (n) ALT 40 U/L (%) 58 (89.2) 13 (20.0) 4 (14.8) 75 (47.8) < ALT > 40 U/L (%) 7 (10.8) 52 (80.0) 23 (85.2) 82 (52.2) Alcoholic (n) ALT 40 U/L (%) 9 (69.2) 3 (15.8) 3 (75.0) 15 (41.7) ALT > 40 U/L (%) 4 (30.8) 16 (84.2) 1 (25.0) 21 (58.3) Total (n) ALT 40 U/L (%) 89 (89.0) 19 (18.6) 8 (22.9) 116 (48.9) < ALT > 40 U/L (%) 11 (11.0) 83 (81.4) 27 (77.1) 121 (51.1) a Fisher s exact or Chi-square test. ALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease. Figure 2. Changes in serum alanine aminotransferase (ALT) levels during the treatment period. Serum ALT levels were rapidly decreased in the pennel group. Serum ALT normalization rates after 4, 8, and 12 weeks were significantly higher in the pennel group than the active and placebo control group. A paired t-test indicated statistical significance ( * ). Figure 3. Changes of serum aspartate aminotransferase (AST) levels during treatment period. Serum AST levels were significantly decreased in the pennel group. However, the changes in serum AST were not significantly different between the pennel and active control groups at 12 weeks. A paired t-test indicated statistical significance ( * ). 간염과바이러스성간염환자에서의미있게 MDA 수치의호전을보였다. 그외에 γ-gtp, ALP, albumin, total bilirubin, total cholesterol 및 triglyceride의변화량을측정하였으나치료 12주째각각의변화량은통계적차이를보이지않았다. 안전성평가전체피험자 237명중 184건의이상반응이발생하였으며 (1명당 0.8건 ), 시험약군, 활성대조군, 위약군간, 발생빈도에대한유의적차이는없었다 (Table 3). 이상반응은대부분 grade 1의경증이었으며 (144/184, 78.3%), grade 3은 1.1% 였다. grade 4 및중대한이상반응은없었다. 시험약과관련이있는경우 ( 명확히있음, 관련이있다고생각됨, 관련성이있을가능성이있음, 관련성이없다고생각됨 ) 는 14건 (17.3%) 이었다. 이상반응이발생하였을때, 시험약을중단없이투여할
7 - Hyung Joon Kim, et al. The efficacy of pennel in chronic liver disease - 수있었으며전체이상반응중 86.4% 가임상시험종료전에해결되었다. 발생빈도, 중상의정도, 시험약과의관련성, 예측가능성, 시험약물투여여부, 처치및결과는각군간유의한차이는없었다. 이상반응이가장많이발생한장기는위장 관계이었으며, 증상으로는감기양증상, 피로, 설사등이었다 (Table 3). 삶의질평가시험약군의 CLDQ 총점수는치료전대비치료 12주에 11.1 (±23.6) 점증가하였다 (Table 4). 평가부분별 CLDQ 점수도시험약군에서일상생활활동도 (activity) 를제외하고통계적으로유의하게증가하였다. 활성대조군도일상생활활동도 (activity) 와고민 (worry) 을제외한나머지부분의점수와총점수가의미있게증가하였다. 반면, 위약군은 12주에향상된부분이없었다. 고 찰 Figure 4. Changes in serum malondialdehyde (MDA) levels during the treatment period. Serum MDA levels were significantly decreased in the pennel group and increased in the active control and placebo groups at 12 weeks. A Wilcoxon's signed rank sum test indicated statistical significance ( * ). 펜넬 (Pennel ) 은 DDB에마늘유 (garlic oil) 를복합시킨제제로그중, Dimethyl-4, 4'-dimethoxy-5, 6, 5', 6-dimethylenedioxybiphenyl-2, 2'dicarboxylate (dimethyl bicarboxylate; DDB) 는오미자열매의성분인 schisandrin C로부터합성한물질로서 [5] 만성바이러스성간염에서혈청 ALT의감소를보인다고보고하고있다. 한편간염의혈청생화학적지표인 ALT Table 3. Adverse events Symptoms Number of cases Pennel (n = 100) Active control (n = 102) Placebo control (n = 35) Total (n = 237) p value a Adverse events Related events Diarrhea Abdominal discomfort Dry mouth Epigastric soreness Rash Poor appetite Indigestion Constipation Chest pain Dizziness Not related b Severe adverse events a Fisher s exact and Chi-square test. b Upper respiratory infection, fatigue, central and peripheral nervous system disorder, musculo-skeletal disorders, benign neoplasm, psychiatric disorder, anemia, urinary system disorder, vascular disorder, vision disorder
8 - 대한내과학회지 : 제 86 권제 2 호통권제 642 호 Table 4. Quality of life assessment in patients with chronic liver disease Change in scores Pennel (n = 100) Active control (n = 102) Placebo control (n = 35) Baseline 12 wk p value a Baseline 12 wk p value a Baseline 12 wk Total CLDQ ± ± ± ± ± ± 27.2 Change from baseline 11.1 ± 23.6 < ± 21.9 < ± Abdominal symptoms 17.6 ± ± ± ± ± ± 3.5 Change from baseline 0.9 ± ± ± Fatigue 23.5 ± ± ± ± ± ± 5.5 Change from baseline 2.9 ± 5.3 < ± 6.4 < ± Systemic symptoms 28.7 ± ± ± ± ± ± 5.0 Change from baseline 1.1 ± ± 4.4 < ± Activity 18.0 ± ± ± ± ± ± 2.6 Change from baseline 1.0 ± ± ± Emotional function 43.4 ± ± ± ± ± ± 9.0 Change from baseline 2.8 ± 7.9 < ± ± Worry 27.2 ± ± ± ± ± ± 7.3 Change from baseline 2.5 ± 6.2 < ± ± CLDQ, chronic liver disease questionnaire. a Wilcoxon's signed rank sum test or paired t-test. b Kruskal-Wallis test. p value a P value b 의증가는간세포의손상을나타내는민감한표지자로알려져있으며 DDB 사용후 ALT의감소는간세포를보호하는효과가있음을간접적으로시사한다. 본연구에서도펜넬투약 12주째 ALT 정상화분율은 89% 로레가론 18.6% 와위약군이 22.9% 에비하여현저하게의미있게높았다. 하위그룹분석인간염의원인에따른분류에서도펜넬군에서통계적으로의미있게 ALT 정상화분율의비율이높았다. 특히 ALT 수치의변화를분석하였을때투약초기시기인첫 4주차에급격하게감소하여투약기간내내 ALT 정상화가유지되어치료반응이빠른속도로, 효과적으로나타났다. 이를토대로 ALT가상승해있는만성간질환자에서펜넬을적어도 4주이상치료할경우효과적으로 ALT의정상화를기대할수있다. 펜넬의간조직의염증완화효과는실험용쥐를이용한동물연구에서입증되었다. 알코올에의한간의지방변성이 DDB 사용후감소하였으며 CCl 4 에의한지질과산화 (lipid peroxidation) 는소포체 (endoplasmic reticulum) 내막에서활성산소 (free radical) 의증가로간손상이발생하지만 DDB 사용후산화물질의감소로간기 능이호전되었음이증명되었다 [14-16]. 본연구에서는혈청 ALT의호전이실제로염증의호전을유도하는지검증하기위하여, 세포막의지질과산화를의미하는 MDA (malondialdehyde) 를측정하였다. 펜넬치료후 12주에레가론, 위약과달리유의하게 MDA가감소하는것을확인하였다. 이러한현상은하위그룹분석에서비알코올성지방간염과바이러스성간염환자에서더욱두드러지게나타났다. 따라서펜넬치료시혈청 ALT의감소가항산화효과와간접적으로연관이있음을생각해볼수있다. 최근우리나라에서비만과관련된대사질환이빠르게증가하고있으며이에따라비알코올지방간질환도 16-33% 의높은유병률을보이고있다. 또한일부의비알코올지방간질환환자에서간경변증이나간세포암과같은말기간질환으로진행할수있다. 2013년대한간학회비알코올지방간질환진료가이드라인에서는치료약제로 ursodeoxycholic acid (UDCA) 와 silymarin 제제, DDB 단독또는복합제제를기술하였으나비알코올지방간질환환자들만을대상으로한연구결과가없어서향후관련연구의필요성을언급하였다 [17,18]. 본연구결과는무작위배정, 이중맹검, 유효성연구로서향
9 - 김형준외 11 인. 만성간질환에서펜넬의임상효과 - 후비알코올지방간질환의진료가이드라인에중요한근거자료로이용될수있을것으로사료된다. 만성바이러스성간염에서도바이러스증식을의미하는 HBV DNA 수치와간손상을의미하는 ALT 수치에근거하여항바이러스제투약을결정하며국가의료보험체계에지원을받는다. 그러나한코호트연구에서는 AST와 ALT의정상상한치를남성은 30 U/L, 여성은 19 U/L로낮추어야한다고제시하였다 [19,20]. 또한다른연구에서도 ALT 가 45 U/L 이하이면서 20 U/L 이상인환자는의미있는간질환의위험이높고간질환의합병증으로사망률도상승함을보고하였다 [21]. 하지만실제로의료현장에서 ALT가 80 U/L 이상상승하지않으면 40 U/L 이상이되어도항바이러스제투약이어려운실정이다. 2011년대한간학회만성 B형간염진료가이드라인이발표되었으나위와같은상황에합당한권고사항은조직검사이외에약제에대한언급이없다 [22]. 비록펜넬의성분중 DDB가만성간질환에서사용했을때조직학적인호전을획득하지못한다고알려져있지만본연구결과가항바이러스제처방기준에합당하지않은환자에게 ALT 호전에도움이되는약제로서근거가되는연구자료로이용될것이다 [7]. Garlic oil은알코올투여전또는동시에투여되었을때에급격한알코올지방간염을효과적으로예방하며그기전은항산화효과로보고하였다 [23]. 본연구의결과도 DDB에의한알코올성지방변성의호전과 garlic oil의항산화효과가알코올간염환자에서의미있게 ALT의호전을유도한것으로판단된다. 동물모델에서도혈액검사와조직검사소견에서화학물질에의한간손상의경우 DDB 단독치료보다는 DDB와 garlic oil 병합치료가더효과적임이증명되었다 [8,9]. DDB가임상에서많이사용됨에도불구하고간세포의손상을막는기전은명확히밝혀지지않았다. 그러나동물모델연구에서 DDB의효과는 NF-κB 활성을막고 TNF-α의생성을억제하여간세포의염증반응을막고 DNA 손상과 caspase 활성의억제를통해간세포사멸을막는다고보고하였다 [24]. 특히항염증효과를증명하는연구로서 CCl 4 를이용하여간손상을일으킨쥐에서 DDB와 garlic oil 병합치료가 Kupffer 세포수와사멸한간세포의수의감소를보고하였다 [25]. 본연구에서항산화효과를평가하기위해 TBARS 와 MDA 두지표를평가하였다. 펜넬을투약하였을때, 비록 TBARS 수치의변화는차이가없었지만 MDA 수치가유의하게감소하여펜넬의항산화효과를임상적으로증명한의미있는연구결과이다. 펜넬약물의안전성평가에서도이상반응의발생빈도가위약군에비해차이를보이지않아안전함이입증되었다. 더욱이이상반응의대부분은감기, 피로, 설사및소화불량등 grade 1의경증이었으며중대한이상반응은없었으며대부분의이상반응이임상시험종료전에해결되어안전한약제로평가되었다. 또한본연구에서각방문시점에서의펜넬투약평균순응도도 90% 이상으로매우높았다. 치료전후피험자의삶의질을평가하기위하여사용한 CLDQ는설문내용이짧고적용하기쉬우며간질환의중등도와연관성이높은것으로알려져있다. 펜넬투여군의삶의질평가총점수가치료 12주에 10점이상증가하였으며레가론이나위약과달리각각의평가부분모두가통계적으로의미있게증가하였다. 단, 연구의제한점으로는치료기간동안체중감소에대한평가와운동량, 음주량등에대한생활습관의변화에대한추가적인평가가부족했다. 결론적으로 ALT가상승한만성바이러스성간질환, 알코올성간질환, 그리고비알코올성지방간질환자를대상으로한, 12주간의펜넬 4상임상시험의유효성과안전성평가에서펜넬은원인질환과무관하게치료 4주만에급격한 ALT 수치의정상화를유도하였으며항산화효과를보였다. 치료기간동안부작용이거의없는안전한약제로서순응도가뛰어났으며, 치료후삶의질이의미있게개선되는효과를보였다. 요약목적 : 펜넬 (Pennel ) 은 DDB에마늘유 (garlic oil) 를복합시킨제제로혈청트랜스아미나제 (AST 와 / 또는 ALT) 가상승된만성간질환자에서펜넬의치료효과에대한유효성을검증하기위해활성대조약인레가론, 위약군과비교평가한다기관제 4상임상연구를실시하였다. 방법 : 총 11개병원, 237명의피험자가연구에참여하였다. 이중시험약군은 100명, 활성대조군은 102명, 위약군은 35명이었다. 12주간의치료기간동안순응도는좋았으며중도탈락은없었다. 환자의연령은평균 46세, 남성의비율이
10 - The Korean Journal of Medicine: Vol. 86, No. 2, 높았다. 치료전 ALT 값은 91 U/L였으며 66% 가비알코올성지방간염, 15% 가알코올성간염, 12% 가만성 C형간염그리고 7% 가만성 B형간염환자였다. 결과 : 약물투약 12주째 ALT 정상화분율은시험약군이 89명으로 89%, 활성대조군이 19명으로 18.6%, 위약군이 8명으로 22.9% 로나타났다 (p < 0.001). 간염의원인에따른분류에서도시험군에서통계적으로의미있게 ALT 정상화분율의비율이높았다. 치료전대비치료 12주의 ALT는시험약군에서평균 85 U/L 감소하였으나활성대조군은 20 U/L, 위약군은 25 U/L 감소하였다. 항산화효과지표인 malondialdehyde (MDA) 는시험약군에서만 1.4 pmol/mg 의호전을보였다. 하위그룹분석에서비알코올성지방간염과, 바이러스성간염환자에서의미있게 MDA 수치의호전을보였다 (p < 0.001). 시험약물의안전성평가에서도이상반응의발생빈도가위약군에비해차이가없었다. 이상반응의대부분은감기, 피로, 설사및소화불량등 grade 1의경증이었으며중대한이상반응은없었다. 삶의질평가총점수도시험약군이치료 12주에 10점이상통계적으로의미있게증가하였다 (p < 0.001). 결론 : 결론적으로 ALT가상승한만성간질환자를대상으로한 12주간의펜넬 4상임상시험의유효성과안전성평가에서펜넬은원인질환과무관하게치료 4주만에급격한 ALT 수치의정상화를유도하였으며항산화효과를보였다. 치료기간동안부작용이거의없는안전한약제로서순응도가뛰어났으며, 치료후삶의질이의미있게개선되는효과를보였다. 중심단어 : 만성간질환 ; 펜넬 ; 트랜스아미나제 ; 임상시험 REFERENCES 1. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19: Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med 1997;336: Fehér J, Lengyel G. Silymarin in the treatment of chronic liver diseases: past and future. Orv Hetil 2008;149: Matveev AV, Koniaeva EI, Kurchenko VP, Shchekatikhina AS. Hepatoprotective properties of silymarin. Eksp Klin Gastroenterol 2011;(2): Xie JX, Zhou J, Zhang CZ, Yang JH, Jin HQ, Chen JX. Synthesis of schizandrin C analogs: II. synthesis of dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylenedioxybiphenyl-2, 2'-dicarboxylate and its isomers (author's transl). Yao Xue Xue Bao 1982;17: Omata M, Yoshida H, Toyota J, et al. A large-scale, multicentre, double-blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut 2007;56: Huber R, Hockenjos B, Blum HE. DDB treatment of patients with chronic hepatitis. Hepatology 2004;39: Kim SG, Nam SY, Chung HC, Hong SY, Jung KH. Enhanced effectiveness of dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylene dioxybiphenyl-2, 2'-dicarboxylate in combination with garlic oil against experimental hepatic injury in rats and mice. J Pharm Pharmacol 1995;47: Park EY, Ki SH, Ko MS, et al. Garlic oil and DDB, comprised in a pharmaceutical composition for the treatment of patients with viral hepatitis, prevents acute liver injuries potentiated by glutathione deficiency in rats. Chem Biol Interact 2005;155: Lee HS, Kim YT, Jung HC, Yoon YB, Song IS, Kim JY. Prospective randomized, controlled trial with diphenyldimethyl-dicarboxylate in chronic active liver diseases: the effect on lowering serum alanine aminotransferase levels. Korean J Med 1991;40: Buzzelli G, Moscarella S, Giusti A, Duchini A, Marena C, Lampertico M. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol 1993; 31: Kim SH, Choi KH, Hwang SG, et al. Validation of the Korean version of liver disease quality of life (LDQOL 1.0) instrument. Korean J Hepatol 2007;13: Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 1999;45: Kim SN, Kim SY, Yim HK, et al. Effect of dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylenedioxybiphenyl-2, 2'-dicarboxylate (DDB) on chemical-induced liver injury. Biol Pharm Bull 1999;22: Lee PY, McCay PB, Hornbrook KR. Evidence for carbon tetrachloride-induced lipid peroxidation in mouse liver. Biochem Pharmacol 1982;31: Muriel P, Alba N, Pérez-Alvarez VM, Shibayama M, Tsutsumi VK. Kupffer cells inhibition prevents hepatic lipid peroxidation and damage induced by carbon tetrachloride. Comp Biochem Physiol C Toxicol Pharmacol 2001;130: Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. J Hepatol 2001;35:
11 - Hyung Joon Kim, et al. The efficacy of pennel in chronic liver disease Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39: Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137: Kariv R, Leshno M, Beth-Or A, et al. Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study. Liver Int 2006;26: Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004; 328: Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2012;18: Zeng T, Guo FF, Zhang CL, et al. The anti-fatty liver effects of garlic oil on acute ethanol-exposed mice. Chem Biol Interact 2008;176: Kim SG, Kim HJ, Choi SH, Ryu JY. Inhibition of lipopolysaccharide-induced I-kappaB degradation and tumor necrosis factor-alpha expression by dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylene dioxybiphenyl-2, 2'-dicarboxylate (DDB): minor role in hepatic detoxifying enzyme expression. Liver 2000;20: El-Bahy AA, Kassem LA, Heikal OA, Mahran LG. Antiapoptotic effect of DDB against hepatic ischemia-reperfusion injury. J Toxicol Sci 2011;36:
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