05-02 최민우

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1 pissn: / eissn: Journal of The Korean Society of Clinical Toxicology 원 저 Amatoxin 중독환자에서 Silymarin, Penicillin, N-acetylcysteine 의효과비교 : 체계적고찰 연세대학교의과대학응급의학교실 최민우 고동률 공태영 좌민홍 유제성 정성필 Comparison of Silymarin, Penicillin, N-acetylcysteine in Patient with Amatoxin Poisoning: A Systematic Review Min Woo Choi, M.D., Dong Ryul Ko, M.D., Taeyoung Kong, M.D., Min Hong Choa, M.D., Je Sung You, M.D., Sung Phil Chung, M.D. Department of Emergency Medicine, Yonsei University College of Medicine, Seoul, Korea Purpose: This study was conducted to evaluate the clinical efficacy of pharmacologic treatment of amatoxin poisoning patients. Methods: Literature was accessed through PubMed, EMBASE, Cochrane library, KoreaMed, KISS and KMBASE. Studies relevant to human use of pharmacologic therapy including silymarin, penicillin and N-acetylcysteine (NAC) for amanita poisoning were included. Case reports, letters, editorials and papers with insufficient information were excluded. Comparison of clinical outcomes (especially mortality and liver transplantation rate) in each study was analyzed. Results: The final analysis included 13 retrospective studies. None of these studies showed direct comparisons of individual agents. Among 12 studies comparing silymarin vs penicillin, eight showed clinical superiority of silymarin. Among eight studies comparing silymarin with NAC, six showed clinical superiority of silymarin. Among seven studies of NAC vs penicillin, five showed clinical superiority of NAC. Conclusion: This systematic review suggested that clinical superiority of various pharmacological agents used to treat amatoxin poisoning is debatable. Nevertheless, the available evidence suggests it is reasonable to consider combinations of multiple agents for patients with amanita poisoning. Further studies are required to establish a treatment regimen for amanita poisoning. Key Words: Amatoxin, Poisoning, Silymarin, Silibinin, Penicillin, Acetylcysteine 서론 책임저자 : 정성필서울특별시강남구언주로 211 연세대학교의과대학응급의학교실 Tel: 02) , Fax: 02) emstar@yuhs.ac 투고일 : 2018년 5월 6일 1차심사일 : 2018년 5월 6일게재승인일 : 2018년 6월 11일 * 이논문은특정단체의재정적지원이나관련된이해관계가없습니다. 국내야생버섯들중식용가능한버섯은 20-30종정도에불과하며, 160여종이상의독버섯이존재한다. 국내버섯중독사망사고의대부분은 amatoxin을함유한독버섯에의한것이다. Amatoxin을함유한독버섯으로는양파광대버섯 (Amanita abrupta), 흰오뚜기광대버섯 (Amanita castanopsidis), 개나리광대버섯 (Amanita subjunquillea), 흰알광대버섯 (Amanita verna), 독우산 J KOREAN SOC CLIN TOXICOL / 33

2 대한임상독성학회지제 16 권제 1 호 2018 광대버섯 (Amanita virosa) 등이있다 1). Amatoxin 중독의치료는보존적치료와약물요법, 투석요법그리고간이식까지다양한치료법이사용되고있다. 이중약물요법의경우 silymarin, penicillin, N- acetylcysteine (NAC) 등이대표적이며이외에도다양한치료약제가단독또는혼합요법으로사용되고있다 2). Silymarin은흰무늬엉겅퀴 (milk thistle) 의추출물로 1) amatoxin의간세포막결합억제, 2) 막간수송에서독소와경쟁적으로작용, 3) 독소의담즙산배설과장내순환억제, 4) 손상된간세포에서의 TNF-α분비억제, 5) 손상된간세포의단백질합성자극기전을통해항독소효과를보인다고알려져있다 3). Penicillin은 Amatoxin 중독에가장많이사용되어온치료제중하나로막수송체인 OATP1B3에경쟁적으로결합하여간내로의 amatoxin 의이동을막는기전을통해항독소효과를보인다고보고있다 4). NAC는 ROS scavenger와 glutathione 전구체로작용하여항독소효과를나타낸다고보고있다 2,5). 저자들은 Amanita species 버섯중독환자를대상으로대표적인 3가지약물요법의치료효용성을알아보기위하여체계적문헌고찰을시행하였다. 대상과방법 1. 문헌검색및선정본연구는기존문헌들의체계적고찰연구로 Preferred Reporting Items for Systematic reviews and Meta- Analyses (PRISMA) 그룹이제시한체계적문헌고찰보고지침에따라수행되었다. 문헌의선정기준은 amatoxin 중독환자를대상으로치료에관한내용이포함된경우로하였다 6). 문헌검색에사용된데이터베이스는 PubMed, Embase, Cochrane library, KoreaMed, Korean Studies Information Service System (KISS), Korean Medical Database (KMbase) 등이었으며데이터베이스에사용한검색식은 Table 1에표기하였다. 검색은두명의연구자에의해시행되었으며, 제외기준으로는 1) 약물투여군과대조군을비교한경우 2) 주제와관련이없는경우, 3) 환자의임상양상이자세히언급되지않은증례보고, 4) 학회초록, 5) 영어나한국어이외의언어로출판된경우 ( 영문초록이있는경우는포함 ) 등은제외하였다. 최종선정된문헌은 EndNote (X8, Thomson Reuters) 에정리하여중복된문헌을제거하였다. 또한문헌에이용된참고문헌들을검토하여빠진문헌이있으면추가하였다. 2. 논문의질평가선택된문헌의질은영국 Scottish Intercollegiate Guideline Network (SIGN) 의체크리스트를이용하여평가하였다. SIGN의질평가도구는연구유형에따라필수항목을선정하고, level 1은메타분석, 무작위대조실험의체계적문헌고찰, 무작위대조실험이해당하고, level 2는환자대조군연구나코호트연구, 또는이를이용한체계적문헌고찰이해당하며, level 3는증례보고같은비분석연구, level 4는전문가의견등이해당된다. 해당 level의조건에모두잘또는적절하게수행되었을경우 ++ 로, 일부항목이불충분할경우 + 로, 대부분충족되지않았을경우 - 로판정하였다 7). 3. 자료의요약필요한항목과문헌에대한간단한요약표를작성하였다. 최종선정된문헌들을검토하여각약제 (silymarin, penicillin, NAC) 각약제간의치료효과를사망및간이 Table 1. Search strategy of databases Database Hits Search strategy PubMed 118 ( poisoning [Mesh] OR intoxication [Mesh]) AND (amanita [Mesh] OR mushroom poisoning [Mesh]) AND (( silibinin [mesh] OR silibinin [all fields]) OR (silymarin OR legalon OR milk thistle) OR penicillins [Mesh] OR acetylcysteine [Mesh]) Embase 500 ( silibinin /exp OR silibinin OR sylimarin /exp OR sylimarin OR penicillin OR acetylcysteine) AND ( amanita /exp OR amanita OR mushroom /exp OR mushroom) AND ([english]/lim OR [korean]/lim) Cochrane library 003 amanita OR amanita phalloides OR Amatoxin KoreaMed 025 (amanita [ALL] or amatoxin [ALL] or mushroom [ALL] ) and (poisoning [ALL] or intoxication [ALL]) KMbase 068 Amanita KISS 027 Amanita * KISS: Korean studies information service system, KMbase: Korean medical database 34 / J KOREAN SOC CLIN TOXICOL

3 최민우외 : Amatoxin 중독환자에서 Silymarin, Penicillin, N-acetylcysteine 의효과비교 : 체계적고찰 식비율을기준으로정리하였다. 결과 1. 문헌검색결과문헌검색을통해 PubMed 118건, Embase 500건, Cochrane library 3건, KoreaMed 25건, KISS 27건, KMbase 68건, 수기검색으로추가 3건이검색되었다. 중복을제외하고제목과초록을검토하여본연구의목적과관련이없는문헌을제외하고 647편을분석하였다 (Fig. 1). 이중관련없는내용을포함한 301편, 증례보고 97편, 치료정보가불충분한연구 33편, 서신 6편, 사설 2편, 영문및한국어이외의언어로저술된 41편, 다른치료법을다룬 28편, 동물대상실험 18편, in-vitro study 11편을제외하고총 13편을대상으로하였다. 논문형식은후향 Fig. 1. Flow diagram according to PRISMA format. J KOREAN SOC CLIN TOXICOL / 35

4 대한임상독성학회지제 16 권제 1 호 2018 적연구 13 편이었다. 고찰 2. 논문의질평가결과 SIGN의질평가도구에의해후향적연구에대하여질평가를시행하였으며, 평가결과 2++ 이 2편, 2-가 11편이었다 (Table 2, 3, 4). 문헌의질평가과정은 2명의연구자에의해수행되었으며, 의견불일치가있는경우는사전에검토원칙을정하였으나연구자간이견은없었다. 3. 치료효과의비교 Silymarin, penicillin, NAC가단일로사용된경우는없었고, 보존적치료와더불어 2가지이상의약제가혼용되어사용된연구가대부분이었다. 각약제간의치료효과를임상적결과 ( 사망률 / 간이식비율 ) 에따라비교분석하였다. 1) Silymarin과 penicillin 간의치료효과비교 12편에서 silymarin과 penicillin 간의치료효과를직간접으로비교가능하였으며, 치료효과간다양한결과가보고되었다 (Table 2). Silymarin이 penicillin보다우월한치료효과를보인다고보고한후향적연구는총 8편으로 silymarin 단일치료또는복합치료로치료에사용한경우에서전반적으로나은임상경과를보고하였다. 4편의후향적연구에서 silymarin과 penicillin 간의치료적우위가동일하거나 (1편), penicillin이더치료적으로우월하다고 (3편) 보고하였다. 2) Silymarin과 NAC 간의치료효과비교 8편에서 silymarin과 NAC간의치료효과를직간접으로비교가능하였으며, 치료효과간다양한결과가보고되었다 (Table 3). 8편중 silymarin의치료효과가우월하다고보고한논문은총 6편이었다. 나머지 2편의논문에서는두약제치료효과간에큰차이가없다고보고하였다. 3) NAC와 penicillin 간의치료효과비교 7편에서 NAC와 penicillin 간의치료효과를직간접으로비교가능하였으며, 치료효과간다양한결과가보고되었다 (Table 4). 이중 NAC의치료효과가우월하다고보고한논문은 5편이었다. 나머지 2편의논문에서는 penicillin이더우월하다고보고하였다. Amatoxin은현재까지가장잘알려진버섯독소로서대부분 cyclopeptides 계열의독버섯에함유되어있다. 현재까지 9가지의 amatoxin이동정되었으며 α-amanitin 은이중생화학적으로활성이가장높은물질이다. 이는 DNA 의존 RNA 중합효소 II를억제함으로서단백질합성을저하시키고결과적으로대사적활발한세포들 ( 위장관세포, 간세포, 신세관세포 ) 에손상을입히게된다. 독소는장상피의 OATP1B3 수용체를통해흡수된후혈장에서빠르게사라지지만, 일부는혈장단백질에약하게결합하여잔존할수있다. 섭취후 48시간이지나면대부분의독소는혈장에서사라지나일부의경우장-간순환 (enterohepatic circulation) 을통해최대 4일까지도남아있을수있는데이를통해흡수, 배설, 재흡수를반복하며간세포의중심소엽괴사 (centrilobular necrosis) 를일으키고이후소변을통한배설과정에서사구체와신세관에흡수되어급성신세관괴사를일으켜간기능부전과신기능부전으로이어지게된다 2,8). Amatoxin 중독에대한치료는일반적약물중독에대한보존적치료와약물요법그리고 molecular adsorbents recirculating system (MARS) 와같은장비의사용, 전격성간부전에대한최종치료인간이식까지다양한치료적접근이이루어져왔다. 약물요법의경우베타락탐계항생제 (benzylpenicilin, ceftazidime), cimetidine, vitamin C, NAC, silymarin 등과함께최근에는 polymyxin B 같은항진균제까지다양한약제가실험적으로사용되고있다. Silymarin은흰무늬엉겅퀴 (milk thistle) 의추출물중 65-80% 를구성하는물질로 7개이상의 flavolignan으로이루어져있다. Silibinin은 silymarin에서상업적으로이용가능한반순수분획물질로두가지부분입체이성질체 (diastereoisomer) 인 silybin A와 silybin B이 1:1로혼합되어있다 9). 본문에인용된논문에서는 silymarin/silibinin/silybin이혼용되어사용되나모두흰무늬엉겅퀴의추출물및유도물질로동일한의미로사용하였다 10). 치료용량의경우각연구별로차이가있으나, 일반적으로정맥주사로 50 mg/kg을 5-24시간동안투여하며치료효과는프로트롬빈시간및혈청간효소수치 (AST/ALT) 의정상화로평가한다 3). 가장흔하게보고되는합병증은위장관부작용이지만대조군에비해전반적인발생률은낮다고알려져있다. 알레르기반응 ( 소양감, 습진, 아나필락시스 ) 은거의없다고알려져있으며, 1,500 mg/day 이상투여시가벼운알레르기반응이있다고보고된바있다 11). Rambaldi 등 12) 이 915명의알코올유발성 36 / J KOREAN SOC CLIN TOXICOL

5 최민우외 : Amatoxin 중독환자에서 Silymarin, Penicillin, N-acetylcysteine 의효과비교 : 체계적고찰 Table 2. Comparison of clinical outcome based on retrospective studies (Silymarin vs penicillin) Author, year Patient group Case/control Outcomes Key results LOE Zilker 20) 154 cases of Amanita species 26 cases (21% of 1632) silymarin only chemotherapy Mortality 0% (Sil alone) poisoning 128 cses (79% of 1,632) silymarin+penicillin chemotherapy vs 9.4% (Sil+Pen) Enjalbert 14) Clinical data from 2018 hospitalized 550 cases (33.7% of 1632) silymarin chemotherapy Mortality 5.4% (Sil) vs 11.6% (Pen) amatoxin poisoning 1411 cases (86.5% of 1,632) penicillin chemotherapy Rengstrorff 23) 8 patients who presented with severe 6 cases (25% of 8) penicillin+nac chemotherapy Mortality and liver 0% (Sil+Pen+NAC) hepatitis after mushroom ingestion 2 cases (25% of 8) penicillin+nac+silymarin chemotherapy transplant vs 0% (Pen+NAC) Krenova 27) 34 patients hospitalized for 5 cases (14.7% of 34) silymarin in the regimen Mortality 20% (Sil) vs 4.3% (Pen) Amatoxin poisoning 18 cases (52.9% of 55) penicillin in the regimen Ganzert 22) Among 604 patients with suspected 118 cases (32.2% of 367) Patients silymarin alone chemotherapy Mortality and liver 5.5% (Sil alone) diagnosis of amatoxin poisoning cases (67.8% of 367) silymarin+penicillin chemotherapy transplant vs 8.8% (Sil+Pen) retrospectively analyzed Zilker 21) 367 cases with suspected diagnosis 118 cases (32.2% of 367) silymarin only chemotherapy Mortality and liver 5.1% (Sil alone) of amatoxin poisoning 249 cses (67.8% of 367) silymarin+penicillin chemotherapy transplant vs 8.8% (Sil+Pen) Poucheret 15) Total 2110 cases : 2018 cases from 624 cases (29.6% of 2110) silymarin chemotherapy Mortality 5.6% (Sil) vs 10.68% (Pen) Enjalbert et al.(2002) report and cases (66.9% of 2110) penicillin chemotherapy complementary cases from the original databases Fix 28) 12 patients presented with ALF due to 3 cases (25% of 12) silymarin in the regimen Mortality and liver 66.7% (Sil) vs 85.7% (Pen) mushroom poisoning 7 cases (58.3% of 12) penicillin in the regimen transplant Ahishali 24) 77 patients hospitalized for mushroom 75 cases (97.4% of 77) penicillin+nac+silymarin chemotherapy Mortality and liver 2.6% (Sil+Pen+NAC) intoxication 2 cases (2.6% of 77) penicillin+nac+chemotherapy transplant vs 0% (Pen+NAC) Roberts 25) 12 patients presented with a history 9 cases (75% of 12) silymarin chemotherapy Mortality 33.3% (Sil) vs 25% (Pen) suggesting Amatoxin poisoning 4 cases (33.3% of 12) penicillin chemotherapy Karvellas 29) A total of 18 patients were identified Unclear Mortality and liver 28.6% (Sil) vs 66.7% (Pen) as having developed severe transplant hepatotoxicity from Amatoxin Trakulsrichai 30) 55 patients with suspected amatoxin- 8 cases (14.5% of 55) silymarin in the regimen Mortality 12.5% (Sil) vs 22.2% (Pen) containing mushroom poisoning 18 cases (32.7% of 55) penicillin in the regimen * LOE: level of evidence, Sil: silymarin, Pen: penicillin, NAC: N-acetylcysteine J KOREAN SOC CLIN TOXICOL / 37

6 대한임상독성학회지제 16 권제 1 호 2018 Table 3. Comparison of clinical outcome based on retrospective studies (Silymarin vs NAC) Author, year Patient group Case/control Outcomes Key results LOE Enjalbert 14) Clinical data from cases (33.7% of 1632) silymarin chemotherapy Mortality 5.4% (Sil) vs 6.7% (NAC) hospitalized amatoxin poisoning 192 cases (11.8% of 1,632) NAC chemotherapy Rengstrorff 23) 8 patients who presented with 6 cases (25% of 8) penicillin+nac chemotherapy Mortality and liver 0% (Sil+Pen+NAC) severe hepatitis after mushroom 2 cases (25% of 8) penicillin+nac+silymarin chemotherapy transplant vs 0% (Pen+NAC) ingestion Poucheret 15) Total 2110 cases : 2018 cases 624 cases (29.6% of 2110) silymarin chemotherapy Mortality 5.6% (Sil) vs 6.8% (NAC) from Enjalbert et al.(2002) report 192 cases (9.1% of 2110) NAC chemotherapy and 2 complementary cases from the original databases Fix 28) 12 patients presented with ALF 3 cases (25% of 12) silymarin in the regimen Mortality and liver 66.7% (Sil) vs 75% (NAC) due to mushroom poisoning 8 cases (66.7% of 12) NAC in the regimen transplant Ahishali 24) 77 patients hospitalized for 75 cases (97.4% of 77) penicillin+nac+silymarin chemotherapy Mortality and liver 2.6% (Sil) vs 0% (Pen+NAC) mushroom intoxication 2 cases (2.6% of 77) penicillin+nac+chemotherapy transplant Roberts 25) 12 patients presented with 9 cases (75% of 12) silymarin chemotherapy Mortality 33.3% (Sil) vs 33.3% (NAC) a history suggesting Amatoxin 6 cases (50% of 6) NAC chemotherapy poisoning Karvellas 29) A total of 18 patients were Unclear Mortality and liver 28.6% (Sil) vs 46.7% (NAC) identified as having developed transplant severe hepatotoxicity from Amatoxin Trakulsrichai 30) 55 patients with suspected 8 cases (14.5% of 55) silymarin in the regimen Mortality 12.5% (Sil) vs 34.3% (NAC) amatoxin-containing mushroom 35 cases (63.6% of 55) NAC in the regimen poisoning * LOE: level of evidence, Sil: silymarin, Pen: penicillin, NAC: N-acetylcysteine 또는바이러스성만성간질환환자를대상으로한 13개의임상시험의체계적고찰에서대조군에비해의미있는유해사례를보이지않았다. 또한 silymarin은 CYP2D6, CYP2E1, CYP3A4의활성을억제할수있으나생리학적농도가임상적으로투여되는농도에비해높아실질적으로투여시이와관련한합병증은유발하기어렵다고알려져있다 13). Silymarin 또는 silibinin은불용성으로대개경구제제로투여하는데, 약제자체의낮은흡수율과인체내짧은반감기로천연물자체의효능을전부발휘하지못한다. Silymarin은경구섭취후 1-2시간내로혈중최고농도에이르고 4-6 시간후제거된다. Legalon-SIL의경우 silibinin의정맥제제로 Amanita 버섯중독의치료로승인된의약품이다 11). Penicillin은전술된 OATP1B3 막수송체에대한경쟁적결합기전이외에도, 알부민과의결합을통한 amatoxin의소변배출증가, 항균작용을통한정상균총감소를통해결과적으로이들에의해생성되는감마아미노뷰티르산 (GABA) 를줄여뇌증예방을하는기전을통해항독소효과를보인다고보고되고있다. 치료용량의경우일반적으로 1,000,000 U/kg의 penicillin G를첫날투여후이후 500,000 U/kg/ day를 2일차부터투여한다고알려져있다 2). 일부치료적효용성이있다고하나다른치료대비높은사망률과전해질불균형, 알레르기반응, 일부신경독성에의한증상등을유발할수있는점을고려해볼때이상적인치료와는거리가멀고, 여러치료옵션중의하나로신중하게투여를고려해야될것으로사료된다. Penicillin과유사한치료기전을보인다고추정되는 3세대 38 / J KOREAN SOC CLIN TOXICOL

7 최민우외 : Amatoxin 중독환자에서 Silymarin, Penicillin, N-acetylcysteine 의효과비교 : 체계적고찰 Table 4. Comparison of clinical outcome based on retrospective studies (NAC vs penicillin) Author, year Patient group Case/control Outcomes Key results LOE Enjalbert 14) Clinical data from cases (11.8% of 1,632) NAC chemotherapy Mortality 6.7% (NAC) vs 11.6% (Pen) hospitalized amatoxin poisoning 1411 cases (86.5% of 1,632) penicillin chemotherapy Poucheret 15) Total 2110 cases: 2018 cases 624 cases (29.6% of 2110) silymarin chemotherapy Mortality 6.8% (NAC) vs 10.68% (Pen) from Enjalbert et al.(2002) report 192 cases (9.1% of 2110) NAC chemotherapy and 2 complementary cases from the original databases Fix 28) 12 patients presented with ALF 8 cases (66.7% of 12) NAC in the regimen Mortality and liver 75% (NAC) vs 85.7% (Pen) due to mushroom poisoning 7 cases (58.3% of 12) penicillin in the regimen transplant Roberts 25) 12 patients presented with 6 cases (50% of 6) NAC chemotherapy Mortality 33.3% (NAC) vs 25% (Pen) a history suggesting Amatoxin 4 cases (33.3% of 12) penicillin chemotherapy poisoning Akin 26) 40 patients with Amatoxin 24 cases (60% of 40) NAC+Standard regimen Mortality 4.4% (NAC) vs 18.7% (Pen) intoxication 16 cases (405 of 40) Standard regimen *Standard regimen: Penicillin+conservative care Karvellas 29) A total of 18 patients were Unclear Mortality and liver 46.7% (NAC) vs 66.7% (Pen) identified as having developed transplant severe hepatotoxicity from Amatoxin Trakulsrichai 30) 55 patients with suspected 35 cases (63.6% of 55) NAC in the regimen Mortality 34.3% (NAC) vs 22.2% (Pen) amatoxin-containing mushroom 18 cases (32.7% of 55) penicillin in the regimen poisoning * LOE: level of evidence, Sil: silymarin, Pen: penicillin, NAC: N-acetylcysteine cephalosporin ceftazidime의경우 penicillin 대체제로거론되고는있으나, 현재까지치료에사용된예가적고사용시대부분 silymarin과같이사용되어순수한 ceftazidime 자체의치료효과를파악하는데편향이있어좀더추가적인연구가필요한약제로생각된다 5,14,15). NAC는아세트아미노펜중독치료에사용되는치료제로 amatoxin 중독과아세트아미노펜중독의임상적유사성 ( 간독성과신독성 ) 으로인해사용되고있는약물요법이다. 치료프로토콜의경우, 1) 15분간 150 mg/kg의투여, 2) 4시간동안 50 mg/kg 투여, 3) 16시간동안 100 mg/kg 순서로투여하게된다. 일부경우에서아나필락시스또는 INR 연장소견을보인다고보고되고있어주의깊은투여가요구되며특별한금기사항이아니라면여러치료방법중의하나로고려해볼수있겠다 2,4,5). Vitamin C의경우지질의과산화에의해발생한간섬유화를억제한다고보고있는데이런기전을통해 amatoxin에의해생성되는활성산소종에의한간괴사를막는다고보고있다. Cimetidine의경우동물실험에서 CYP450 효소들을억제하여최종적으로간세포괴사와간세포의미토콘드리아손상을막는다고보고되고있으며해당기전을통해 amatoxin에의한간독성을억제한다고보고있다. Vitamin C나 cimetidine의경우대규모로시행된치료효용성비교연구는없으며 acetaminophen이나 CCl 4 에의한간독성을억제하던기전에착안하여 20년전부터다른치료요법의일부로포함되어경험적으로사용되었다 14). 치료효용성을비교할만한적절한연구가불충분하여다른치료약제가있는현재에는 1차적으로고려할대상은아닌것으로사료된다. 최근 in-vitro 연구및동물실험연구에서연구중인 polymyxin B의경우 α- amanitin이결합하는 RNA 중합효소 II에경쟁적으로결합하여독소의작용을방해한다고보고있으며, 해당기전으로간및 J KOREAN SOC CLIN TOXICOL / 39

8 대한임상독성학회지제 16 권제 1 호 2018 신장의α-amanitin에의한손상을상당히줄인다고보고되고있다 16). 약물요법으로해결되지않은간부전의경우결국간이식을필요로하게되는데, 간이식까지의교가요법으로 Molecular Adsorbent Recirculating System (MARS ) 또는 Fractionated Plasma Separation and Adsorption System (FPSA, Prometheus ) 등이있다. 이는현재까지중독에의한급성간부전치료에임상적효과를보인다고보고되고있다. 전반적인기전을알부민결합독성물질및친수성분자를기존의투석을통해독성물질을인체에서제거하게된다 17,18). 문헌고찰의대상이된세약제중 NAC, penicillin의경우국내모두정맥제제및경구제제처방이가능하나, 미국의경우정맥주사제가사용되고있는 silymarin은국내에서는사용가능한정맥제제가없고, 경구용 silymarin 인 Legalon 캡슐 ( 현재 70 mg, 140 mg 단위로처방가능함 ) 이시판중이다 1,19). 문헌고찰결과단일약제치료와다른단일치료간의직접비교를시행한연구는없었으며, 다른약제와병합치료를통한비교연구가대부분이었다. 검색된후향적연구들대부분은 100명이하의적은그룹을대상으로시행된연구이고, 연구대상약제투여군과비투여군간의수차이가큰경우가많아통계적비교가어려운경우가많았다. 1) Silymarin과 penicillin 간의치료효과비교비교분석한 12편의연구중 8편에서 silymarin의더나은임상적결과를보였으나일부연구에서는결과해석에여러제한점이존재했다. Silymarin이치료적으로우위를보고한연구중 Zilker 등 20,21) 의연구과 Ganzert 등 22) 의연구는 silymarin 단독요법과 silymarin+penicillin 요법간의비교로 silymarin 단독요법의낮은사망률을근거로 silymarin이 penicillin에비해치료적으로우월하다고보고한연구였다. 허나이는 Silymarin과 penicillin 간의상호작용에의한치료효과저하가능성도있어연구결과해석에제한점이있다고본다. 두약제간치료효과가비슷하거나, penicillin이더우위에있다고보고한 Renstroff 등 23) 의연구와 Ahishali 등 24) 의연구의경우 silymarin+ penicillin+nac 치료군과 Penicillin+NAC 치료군을비교한것으로 Penicillin과 NAC 간의영향여하를완전히분리할수없어이또한연구결과해석의제한점으로생각된다. 2) Silymarin과 NAC 간의치료효과비교비교분석한 8편의연구중 6편에서 silymarin의더나 은임상적결과를보였으나일부연구에서는결과해석에여러제한점이존재했다. Roberts 등 25) 이 12명의 Amatoxin 중독환자를대상으로한연구에서는 silymarin, penicillin, NAC 등이혼재되어사용되어결과론적으로는 silymarin과 NAC의치료효과가비슷하다고보고하였으나약제간의상호영향을완전히배제할수없는제한점이있었다. 3) NAC와 penicillin 간의치료효과비교비교분석한 7편의연구중 5편에서 NAC가더나은임상적결과를보였다. NAC의치료적우위를보고한연구중 Akin 등 26) 이 40명의 Amatoxin 중독환자를대상으로시행한연구의경우보존적치료를공통적으로시행하는전제하여 penicillin 치료군과 NAC 치료군을비교한것으로분석대상중외부적인요소를가장잘배제하여약제간의비교가매우용이한연구로생각된다. 본연구는여러제한점을가지고있다. 첫째, 후향적연구로환자간의자세한병력비교가어려우며일부연구의경우치료군과대조군의수차이가커치료효과의비교가어려웠다. 둘째, 치료에사용된약물의용량및투여방법이서로다르고일부논문의경우이에대한정확한내용파악이어려워치료간의정량적비교가어려웠다. 셋째로대부분의단일약제간의비교를한경우는없고다른약제와함께연구대상약제가포함된병합치료와연구대상약제가포함되지않은병합치료간의비교로다른약제및치료방법에의한영향여하를명확히구분할수없다는점이었다. 마지막으로출판된좋은결과만을근거로결론을내리게되는출판편향 (publication bias) 이있을수있는점이었다. 결론 Amanita 중독의치료에대한체계적고찰결과높은근거수준으로뒷받침되는치료방침은없는상태이다. 비교대상이된연구들은대부분약제간의직접비교가원활하지않고출판편향의가능성이높아명확한치료상의이점을추정하기어렵다. 따라서추후더많은연구결과를기다릴필요가있으며, 그때까지는보존적치료와더불어 silymarin, penicillin, NAC 등의치료법을고려하는것이필요하다. ORCID Min Woo Choi ( 40 / J KOREAN SOC CLIN TOXICOL

9 최민우외 : Amatoxin 중독환자에서 Silymarin, Penicillin, N-acetylcysteine 의효과비교 : 체계적고찰 Sung Phil Chung ( 참고문헌 01. Sohn CH. Type and treatment of toxic mushroom poisoning in Korea. J Korean Med Assoc 2015; 58: Smith MR, Davis RL. Mycetismus: a review. Gastroenterol Rep 2016;4: Mengs U, Pohl RT, Mitchell T. Legalon SIL: the antidote of choice in patients with acute hepatotoxicvity from amatoxins poisoning. Curr Pharm Biotechnol 2012;13: Ye Y, Liu Z. Management of Amanita phalloides poisoning; A literature review and update. J Crit Care 2018;46: Garcia J, Costa VM, Carvalho A, Baptista P, de Pinho PG, de Lourdes Bastos M, et al. Amanita phalloides poisoning: Mechanisms of toxicity and treatment. Food Chem Toxicol 2015;86: Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62: Available at: html. Accessed April 13, Berger KJ, Guss DA. Mycotoxins revisited: part I. J Emerg Med 2005;28: Polyak SJ, Oberlies NH, Pecheur EI, Dahari H, Ferenci P, Pawlotsky JM. Silymarin for HCV infection. Antivir Ther 2013;18: Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver disease. Drugs 2001;61: Post-White J. Advances in the use of milk thistle. Intergrr Cancer Ther 2007;6: Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev 2005;2:CD Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, et al. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002;16: Enjalbert F, Rapior S, Nouguier-Soule J, Guillon S, Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002;40: Poucheret P, Fons F, Dore JC, Michelot D, Rapior S. Amatoxin poisoning treatment decision-making: Pharmacotherapeutic clinical strategy assessment using multidimensional multivariate statistic analysis. Toxicon 2010;55: Garcia J, Costa VM, Carvalho AT, Silvestre R, Duarte JA, Dourado DF, et al. A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Arch Toxicol 2015;89: Rifai K, Ernst T, Kretschmer U, Bahr MJ, Schneider A, Hafer C, et al. Prometheus--a new extracorporeal system for the treatment of liver failure. J Hepatol 2003;39: Pillukat MH, Schomacher T, Baier P, Gabriels G, Pavenstadt H, Schmidt HH. Early initiation of MARS(R) dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation. Ann Hepatol 2016;15: Available at: Accessed May 20, Zilker TR, Felgenhauer NJ, Michael H, Strenge-Hesse A. Grading of severity and therapy of 154 cases of Amanita poisoning. Vet Hum Toxicol 1993;35: Zilker TH. Prognosis and treatment of amatoxin poisoning. Clin Toxicol 2009;47: Ganzert M. Felgenhauer N. Schuster T, Eyer F, Gourdin C, Zilker T. Amanita poisoning-conparison of silibinin with a combination silibinin and penicillin. Dtsch Med Wochenschr 2008;133: Rengstorff DS, Osorio RW, Bonacini M. Recovery from severe hepatitis caused by mushroom poisoning without liver transplantation. Clin Gastroenterol Hepatol 2003;1: Ahishali E, Boynuegri B, Ozpolat E, Surmeli H, Dolapcioglu C, Dabak R, et al. Approach to mushroom intoxication and treatment: can we decrease mortality? Clin Res Hepatol Gastroenterol 2012;36: Robert DM, Hall MJ, Falkland MM, Strasser SI, Buckley NA. Amanita phalloides poisoning and treatment with silibinin in the Australian capital territory and New South Wales. Med J Austr 2013;198: Akin A, Keskek SO, Kilic DA, Aliustaoglu M, Keskek NS. The effect of N-acetylcysteine in patients with Amanita phalloides intoxication. J Drug Metab Toxicol 2013;4: Krenova M, Pelclova D, Navratil T. Survey of Amanita phalloides poisoning: clinical findings and follow-up evaluation. Hum Exp Toxicol 2007;26: Fix OK, Davern TJ, Doo E, Zaman A, Ganger DR, Reddy R, et al. Acute liver failure due to mushroom poisoning in the United States: Results from the ALFSG registry. Hepatology 2011;54:497A. 29. Karvellas CJ, Tillman H, Leung AA, Lee WM, Schilsky ML, Hameed B, et al. Acute liver injury and acute liver failure from mushroom poisoning in North America. Liver Int 2016;36: Trakulsrichai S, Sriapha C, Tongpoo A, Udomsubpayakul U, Wongvisavakorn S, Srisuma S, et al. Clinical characteristics and outcome of toxicity from Amanita mushroom poisoning. Int J Gen Med 2017;10: J KOREAN SOC CLIN TOXICOL / 41

김범수

김범수 Analysis of Outcomes after Resection of Sarcomatous Hepatocellular Carcinoma Purpose: Sarcomatous hepatocellular carcinoma (HCC) is rare. Therefore, the clinicopathologic characteristics and prognosis