Molsidomine, Nicorandil, Trimetazidine의 안전성 관련 체계적 고찰

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Molsidomine, Nicorandil, Trimetazidine의 안전성 관련 체계적 고찰 한국임상약학회지 제26권 제2호 Korean Journal of Clinical Pharmacy Korean J Clin Pharm, Vol. 26, No. 2, 2016 Official Journal of Korean College of Clinical Pharmacy Original Article Available online at http://www.kccp.or.kr pISSN: 1226-6051 Molsidomine, Nicorandil, Trimetazidine의 안전성 관련 체계적 고찰 정경혜1·김은경2* 1중앙대학교 약학대학, 2서울대학교 약학대학 (2016년 4월 19일 접수·2016년 5월 20일 수정·2016년 5월 20일 승인) A Systematic Review on Drug Safety for Molsidomine, Nicorandil and Trimetazidine Kyeong Hye Jeong1 and Euni Lee2* 1College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea 2College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea (Received April 19 2016·Revised May 20 2016·Accepted May 20 2016) ABSTRACT Background: Ischemic heart disease is the most common type of heart disease and an important cause of death in Korea. Among marketed anti-anginal medications, molsidomine, nicorandil, and trimetazidine are approved in Korea with unique mechanism of actions. As these drugs are not approved by the US Food and Drug Administration, the access to the up-to-dated and comprehensive safety-related information has been less than optimal from drug information resources used by Korean pharmacists. Methods: A systematic review was conducted using Embase and Korean manuscripts to compile safety updates for these medications. Out of 418 articles from keyword searches, 52 studies were reviewed in full to compare adverse effects (AEs) with the approved package inserts (PI). Results: Molsidomine related adverse effects were mostly mild or moderate, but anxiety, palpitation, epigastric pain, and sexual potency reduction were additional AEs found from the review not listed in PI. Although PI has included ulceration in oral cavity and gastrointestinal tracts including anus by nicorandil, the Korea FDA recently recommended adding corneal, genital, and skin ulcers to the approved PI. Trimetazidine induced Parkinsonism, worsening of the symptoms for patients diagnosed with Parkinson's disease, gastrointestinal burning, and muscle cramps were additionally identified AEs not listed in PI for trimetazidine. Conclusion: Continuous evaluations of the safety profile of these agents are needed to balance the risks and benefits to provide evidence-based safety counseling to the patients. In addition, more focused efforts on spontaneous reporting are warranted by healthcare professionals to safeguard patients against AEs. KEY WORDS: Molsidomine, nicorandil, trimetazidine, safety, adverse effects 한국인의 평균수명은 2005년 78.6세에서 2014년에는 82.4 하는 대표적 허혈성 심장 질환의 하나로, 적절한 치료가 시행 세로 증가하였으며 1) 심장 질환의 유병률도 2005년 인구 10 되지 않으면 심근경색으로 진행되어 사망률을 높이는 주요 원 만명당 39.3명에서 2014년 52.4명으로 증가했다.2) 또한 심장 인이 된다. 약물요법은 이러한 협심증의 중요한 치료 방법으 질환의 치료에 소요되는 연도별 의료비의 지출은 2009년 로 고려되고 있다. 협심증 치료에 사용되는 대표적 약물은 β- 1,233,209원에서 2012년 1,630,480원으로 상승했다.3) 이와 같 adrenergic blockers, calcium channel blockers, nitrates, 이 인구의 고령화가 빠르게 진행되고 그에 비례한 심장 질환 ivabradine, molsidomine, nicorandil, trimetazidine 등이 있으 의 유병률 증가로 국가차원 의료비 부담이 가중되고 있다. 며, 이중 molsidomine, nicorandil, trimetazidine은 미국 Food 통계청 발표자료에서 심장 질환은 2014년 한국인 사망원인 and Drug Administration (FDA)에 의해 승인되지 않은 약물 중 2위를 차지했으며, 심장 질환 중에서 허혈성 심장 질환 이다. (Ischemic heart disease)의 사망률이 50세 이상에서 가장 높은 Molsidomine (SIN-10, N-ethoxycarbonyl-3-morpholino- 것으로 나타났다.4) 협심증은 관상동맥의 산소 부족으로 발생 sydnonimine)은 1980년 독일에서 개발되어 1995년 11월에 국 *Correspondence to: Euni Lee, College of Pharmacy, Seoul National University, Gwanak-ro 1, Gwanak-gu, Seoul 08826, Republic of Korea Tel: +82-2-740-8588, Fax: +82-2-880-9122 E-mail: [email protected] 172 Molsidomine, Nicorandil, Trimetazidine의 안전성 관련 체계적 고찰 / 173 내에서 승인되었다. Molsidomine은 prodrug으로 간에서 SIN- 연구 방법 1 (Linsidomine, 3-morpholino-syndnonimine)으로 대사된 후 혈관 평활근으로 들어가 활성 대사체인 SIN-1A (N-nitroso- 2015년 12월 31일까지 접근 가능한 국내논문과 Embase 자 N-morpholino aminoacetonitrile)로 전환된다. SIN-1은 혈소판 료를 사용하여 총 3개 약물(molsidomine, nicorandil, trime- 억제 작용을 나타내며 SIN-1A는 NO donor로 nitric oxide를 tazidine)을 대상으로 PRISMA 2009 guideline을 따라 검색과 방출하여 cyclic guanosine monophosphate (c-GMP)를 증가 고찰을 수행하였다. 자료수집은 PICOS 영역에 따라 진행하여 시켜 혈관을 확장한다. SIN-1은 guanylate cyclase를 활성화하 study participant는 ‘human’(P), intervention은 해당약물(I), 기 위해서 sulfhydryl group과 결합해서 S-nitrosothiols 형태로 comparison group(C)은 placebo, 타의약품을 포함하였고, out- 변화되어야 하는 nitrate와 달리 직접 nitric oxide를 방출하므 come(O)은 ‘safety’, ‘adverse events’, ‘adverse effects’, ‘side 로 내성이 발현되지 않는 장점이 있다고 알려졌다.5) effects’의 검색어를 사용하였다. 비교군이 있는 연구디자인은 Nicorandil은 1975년 일본에서 합성되어 1984년 5월에 일본 물론 비교군이 없는 연구디자인(S), 즉 case report 혹은 case 에서 승인되었으며 1985년 12월 국내에 승인되었다. Nicorandil series, review 연구물도 포함하여 검색하였다. ‘English’로 쓰 은 nitrate 유사작용과 칼륨 이온 통로 활성화의 두 가지 작용 여지고 출판된 논문으로 제한하여 1차 검색하였고, 검색된 문 기전을 갖고 있는 nicotinamide nitrate이다. Nitrate와 유사하 헌들은 초록을 확인하여 안전성 연구에 해당하는 필요 문헌을 게 nitrate oxide 생산으로 guanylate cyclase를 활성화해서 c- 추출하였고, 본 연구에 적합성은 2명의 연구자(KHJ, EL)가 합 GMP를 증가시킴으로써 정맥과 관상동맥을 확장시킨다.6) 또 의한 후 최종으로 문헌선정을 진행하여 원문을 확보하여 종합 한 심장 평활근에서 ATP 의존적 칼륨 이온 통로를 활성화시 적인 검토를 하였다. 켜 칼륨 이온 유출을 증가시키고 칼슘 이온 유입은 감소시키 모든 논문은 논문의 연구설계방법에 따라 experimental 며 sarcoplasmic membrane으로부터 칼슘 이온 방출을 억제하 study (randomized controlled trial, quasi-experimental study), 여 동맥을 확장한다.7) observational study (cohort study, case-control study, cross Trimetazidine(1-[2,3,4-trimethoxybenzyl]-piperazine)은 1978 sectional study), case-series study 혹은 case report, review 연 년 프랑스에서 처음 허가 되었고 국내에는 1986년 9월에 허가 구로 분류하여 각각의 연구물에서 도출된 결과가 연구설계방 되었다. 다른 협심증치료제와 구별되는 독특한 기전을 가진 법에 따른 타당성의 수준에 맞추어 해석되도록 하였다. 본 연 trimetazidine은 대부분의 협심증 치료약물과 달리 혈관이나 구는 출판된 논문을 중심으로 연구를 진행하였기 때문에 체계 심박수에 영향을 주지 않고 허혈로 인한 손상으로부터 심근을 적인 자료수집 외 개별적으로 발견된 논문이나 grey literature 보호하는 역할을 한다.8) 또한 3-ketoacyl-CoA thiolase를 저해 등은 포함하지 않았다. Embase와 같은 국외출판논문 외 국내 하여 유리지방산의 β-oxidation을 감소시키고 포도당 산화를 논문자료를 포함하여 publication bias의 규모를 축소하고자 촉진함으로써 산소소비량을 감소시키며, 미토콘드리아 내 하였다. 본 연구는 각 약물의 허가사항 제품정보에 기재되어 free radical을 감소시켜 대사 이상으로부터 심장을 보호한다.9) 있지 않은 이상반응을 중점적으로 수집하고 분류하여 비교분 국내 의료서비스 제공자가 용이하게 접근할 수 있는 Lexi- 석하고 추가 부작용을 요약하였다. comp® 혹은 UpToDate® 등과 같은 의약품정보원은 미국 FDA에서 승인을 받은 의약품에 대하여 비교적 구체적인 안전 연구 결과 및 고찰 성 정보를 시의 적절하게 업데이트하지만 이 3가지 약물과 같 은 약물은 international drug information항으로 구별하여 축 미국 FDA에서 승인되지 않은 molsidomine, nicorandil, 약된 정보를 제공하므로 국내 약사나 의료서비스 제공자가 고 trimetazidine의 약물에 대하여, 승인이 이루어진 우리 나라에 려해야 할 안전성 정보는 다소 제한적일 수 있다. 그러므로 본 서 해당 약물의 안전성을 체계적으로 고찰함으로써, 본 의약 연구는 심장질환 환자를 대상으로 하여 molsidomine, nico- 품의 package insert의 정보를 업데이트하고, 이를 통하여 의사 randil, trimetazidine을 placebo 혹은 타 약물과 안전성 비교연 와 약사가 효율적인 약물치료와 복약지도를 각각 수행할 수 구를 수행한 연구물 혹은 사례연구 문헌조사를 체계적으로 수 있도록 본 연구를 수행하였다. 국내문헌조사에서 해당약물의 행하여 최신의 약물이상반응 정보를 제공하며 허가사항 제품 안전성과 관련된 논문은 검색되지 않았으므로 국외논문에 초 정보에 기재된 정보와 비교 검토하여 추가수정이 요구되는 이 점을 맞추어 진행하였다. 초기문헌검색에서 확인된 국외문헌 상반응을 보고하여 궁극적으로 의사 혹은 약사들이 최신 자료 은 총 418편으로, molsidomine 78편, nicorandil 209편, trim- 를 바탕으로 환자와 상담하고 복약지도를 제공하는 것을 연구 etazidine 131 편의 문헌이 검색되었다. 이중 초록 검토를 통해 목표로 한다. 약물의 안전성과 관련이 없는 문헌과 원문을 찾을 수 없는 문 헌을 제외하여 총 60편의 문헌(molsidomine 8편, nicorandil 34 174 / Korean J Clin Pharm, Vol. 26, No. 2, 2016 로 진행된 코호트 연구인 PEM study에서는 두통과 현기증 (dizziness)이 가장 빈번하게 발생한 이상반응이었으며 nico- randil 복용 중단의 주요 원인으로 제시 되었다. 이 연구에서 55건의 구강궤양(mouth ulcers) 발생이 보고되었다.14) 1997년 프랑스에서 구강궤양이 처음 보고되었고 이후 구강 뿐만 아니라 신체 여러 부위에서 궤양이 발생하였음이 보고되 었다.15) 구강궤양이 발생한 부위는 혀, 잇몸, 볼, 경구개, 입술, 인후 등이며 16) nicorandil 복용 직후부터 수년 사이에 발생하 였다. 국소 steroid 등의 치료로 완화되지 않았으며 nicorandil 복용을 중단한 후에 사라졌다. 궤양은 보통 nicorandil 1일 40- 60 mg 용량에서 발생하지만 1일 10 mg 용량에서도 발생이 보 고되었다.17) 1일 20 mg 이상의 용량을 사용하는 유럽에서보 다 1일 15 mg (국내와 동일 용량)을 사용하는 일본에서 이상반 응이 적게 보고된 것은 구강궤양이 용량의존적으로 발생이 증 15) Fig. 1. The PRISMA flow chart of the article selection process and 가하기 때문인 것으로 시사되었다. 구강 외 다른 부위에서 reasons for exclusions. 의 궤양 발생도 보고되었다. Nicorandil 1일 20 mg을 3년 복용 후 콧등에 발생한 궤양은 nicorandil을 중단 1달 후 완화되기 편, trimetazidine 18편)을 선정하여 전문을 검토하였다. 그 중 시작해서 4달 만에 치료되었다는 보고가 있다.18) 또한 결막과 유효성만 언급된 논문과 해당 연구 약물로 인한 직접적인 부 각막에 궤양 발생과 위장관(회장 말단, 결장), 항문과 그 주변, 작용이 언급되어 있지 않은 논문을 제외하고 총 52편(molsi- 외음질(vulvovaginal), 성기(penile)에서의 궤양 또한 보고되었 domine 7편, nicorandil 31편, trimetazidine 14편)의 문헌을 최 다.19) 궤양이 유발되는 정확한 원인은 알려져 있지 않으나 수 종선정 문헌으로 추출하여 해당 약물의 안전성에 관해 조사하 개월 동안 nicorandil을 사용한 후에 nicotinamide, nicotinic 였다(Fig. 1). 체계적인 검토로 확인된 약물의 이상반응 항목 acid가 축적되고 비정상적으로 분포되어, 피부와 점막을 통해 들은 연구설계방법 별로 요약하였고(Table 1), 허가사항 제품 일어나는 재상피화(re-epithelialization) 과정이 손상되기 때 정보에 기재된 이상반응과 본 고찰연구에서 발견된 허가사항 문에 발생한다는 가설이 있다.20,23) 2016년 1월 21일에 nico- 제품정보에 기재되지 않은 이상반응은 비교하여 표로 요약하 randil 국내 허가사항이 변경 고시되었고, 그 결과 ‘각막궤양, 였다(Table 2). 분석에 포함한 연구들에 대한 요약은 Table 3에 성기궤양, 피부궤양, 복시, 고칼륨혈증, 경부통이 나타날 수 있 제시했다. 다’는 내용이 추가되었다. 이미 기재되었던 구내염, 혀 궤양, 항 Molsidomine으로 인한 심각한 이상반응은 보고되지 않았으 문궤양, 위장관 궤양에 각막, 성기, 피부에 나타나는 궤양이 추 며 대부분 경증, 증등도의 두통과 저혈압이 일반적인 이상반 가된 것으로, 최근 발표된 부작용 발생양식을 감안한 시기 적 응으로 나타났다.
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