전재범등 : 전신성항진균제와임상적이용 대한의진균학회지제 10 권제 1 호 2005 초청원고 전신성항진균제와임상적이용 울산대학교의과대학서울아산병원감염내과학교실 전재범 최상호 류지소 우준희 =Abstract= Systemic Antifungal Agents and Clinical Application Jae Bum Jun, Sang Ho Choi, Ji So Ryu and Jun Hee Woo Division of Infectious Disease, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea In the past, even two decades ago, it was not easy for the physicians to diagnose the systemic fungal infection especially in immuno-compromised host. However, as malignant neoplasm and organ transplantation increased, the incidence of fungal infection became heightened. Also the development of newer technique of microbiology and computerized imaging methods made it relatively easy to diagnose the fungal infection. Several new antifungal agents developed recently. It is necessary for us to prescribe the antifungal agents optimally. We summarized amphotericin B lipid formulations, newer triazoles, echinocandins. [Kor J Med Mycol 2005; 10(1): 1-10] Key Words: Liposomal amphotericin B, Voriconazole, Caspofungin 서 론 진균감염의진단이영상의학기술과분자의학의발달로과거에비하여상대적으로쉬워졌고악성종양환자와장기이식환자의증가에따라필연적으로진균감염이증가하여이를치료하기위한약제의필요성이증가되었다 1,2. 저자들은 5년전에이미새로이등장하게될전신성항진균제와그필요성을논의한바있고 3,4 그후등장한항진균제들의임상적응용을정리하여보고자한다. 전신성항진균제는크게 4개의군으로나눌수있는데 polyene계 (amphotericin B nystatin), pyrimidine계 (Flucytosine), azole 별책요청저자 : 우준희, 143-914 서울특별시송파구풍납동 388-1, 울산대학교의과대학서울아산병원감염내과학교실전화 : (02) 3010-3300, Fax: (02) 3010-6970 e-mail: junheewoo@amc.seoul.kr r 계 (ketoconazole itraconazole) 그리고최근에개발된 echinocandin계등이다. 1950년대말 polyene계인 amphotericin B가처음으로임상에서사용된이래전신성항진균요법의표준요법 (gold standard) 로널리쓰여왔다. 하지만 amphotericin B의정주시발생하는열, 오한, 오심, 구토같은부작용과신독성때문에사용이제한되는경우가많았고경구용제제가없는단점이있었다. 이러한문제점들때문에새로운항진균제를찾기위한연구가계속되었고 1970 년대초 azole계인 clotrimazole이경구용제재로처음개발되었고 5 이후 miconazole, ketoconazole 등이개발되었으나부작용, 약물상호작용, 낮은치료효능등으로널리사용되지못하다가 1990년대초반 fluconazole, itraconazole 등의 triazole이등장한이후 6 현재까지광범위하게사용되고있다. 하지만최근 20년간 HIV 감염증, 항암화학요법, 골수이식, 장기이식, 장기적인스테로이드의사용등과관련된면 - 1 -
대한의진균학회지제 10 권제 1 호 2005 역저하환자들이늘어나면서침습적진균감염이급속도로증가하였고이와더불어항진균제에대한내성 3,7 침습적 aspergillosis에서의높은치료실패율등이문제가되고있어이런문제들을극복할수있는새로운항진균제에대한필요성이증대되었다 1,4. Lipid formulations of amphotericin B 1980년대초에동물실험을통한연구들에서 amphotericin B lipid formulation이독성이적고치료지수 (therapeutic index) 가높다는것이밝혀지면서 8~10 amphotericin B lipid formulation에관한연구가지속되어현재의 (1) AmB colloidal dispersion ([ABCD] Amphocil or Amphotec) (2) AmB lipid complex ([ABLC] Abelcet) (3) a small unilamellar vesicle liposomal formulation ([L-AmB] AmBisome) 의 3가지약이미국식약청 (FDA) 의허가를받아사용되고있다. 1. 구조 Amphotericin B lipid formulation의구조는 amphotericin B가 phospholipid와 1:1 drug-to-lipid 분자구조로결합되어있는모양인데, 3가지약에따라각각 phospholipid의종류와크기가달라 3차원적구조가달라진다. 예를들면 ABLC는 1-α-dimiristoyl-phosp- hatidylcholine (DMPC), 1-α-dimiristoyl-phosphatidylglycerol (DMPG) 의 2가지종류의 phospholipids가 amphotericin B와결합된구조로 3차원적으로리본모양을하게된다 (Fig. 1). 2. 작용기전 Amphotericin B의주작용기전은진균의세포막을형성하고있는 ergosterol에결합하여막의파열을초래하고투과성을증가시켜세포질내성분이누출되게함으로써세포를사멸하게하는것이다 11. 하지만결합정도는약하지만사람의 cholesterol에도부착하게되어부작용을일으킨다. 자유라디칼 (free radical) 형성과관련된산화적손상으로살진균작용을일으킨다는보고도있다 12. 3. 약물동력학 Amphotericin B lipid formulation은기존의고도친지질성 (lipophilic) 인 amphotericin B deoxycholate (AmB-D) 보다물에서의용해도가높고효소에의한분해속도가느려주입 (infusion) 간격을연장시킬수있고치료지수도높다 13. 3가지약에따라혈장내반감기, 최고혈장농도등이각각다르지만공통적으로폐간비장등의세망내피계 (reticulo-endothelial system) 에광범위하게분포되는특징이있고신장에 Fig. 1. The putative structure of ABLC. Amphotericin and lipid are arranged in a 1:1 interdigitated complex. - 2 -
전재범등 : 전신성항진균제와임상적이용 는거의분포되지않고 14 주입 (infusion) 관련부작용이적은점등의기존의 AmB-D와다른면이있다. 그리고 AmB-D에비해하루용량을 10배까지증량시킬수있으나 15 최적하루용량및총사용량등은아직확립되지않았다. 4. 항진균작용및임상적적용 AmB-D는 C. lusitaniae를제외한 Candida spp와 C. neoformans에서는내성이드물고 aspergillus에서는다양한감수성을보인다. 하지만 Aspergillus terreus, Fusarium spp, Pseudallescheria boydii, Scedosporium prolificans, Trichosporon beigelii에서는내성이흔하다 16. AmB-D와 3가지의 lipid formulation을비교한임상연구들을보면 amphotericin B lipid formulation은 AmB-D에비해서적어도동일한치료효과를보였고신독성은감소된결과를보였으며 L-AmB에한해서는발열오한등의주입관련부작용들도적은것으로나왔다 17,18. 지속되는호중구감소성발열환자 702명을대상으로한대규모무작위대조군임상 시험연구에서 L-AmB (3.0 mg/kg/day) 치료군에서 AmB-D (0.6 mg/kg/day) 치료군에비해치료중진균감염 (breakthrough infection) 과약물부작용의의미있는감소를보였다 19. Lipid formulation 간에서로를비교한연구들이있었지만이연구들만으로는서로간의치료효능을비교하기는힘들었다 18. AmB-D에감수성이있지만치료에반응을하지않는침습적진균감염의치료제로 3가지약모두 FDA의허가를받았고 L-AmB에한해서는지속되는호중구감소성발열환자에서의경험적치료제로 FDA의허가를받은상태이다. New Triazoles: Voriconazole, Ravuconazole, Posaconazole Voriconazole 1. 구조및작용기전 제 2 세대 trizole 로서 voriconazole 과 ravuconazole Fig. 2. Structural formulas of systemic antifungal triazoles itraconazole, fluconazole, posaconazole, voriconazole, and ravuconazole. - 3 -
대한의진균학회지제 10 권제 1 호 2005 은 fluconazole의유도체이고 posaconazole은 itraconzole의유도체이다 (Fig. 2). Azole계의항진균제는진균의 cytochrome P450 의존성 lanosterol 14-α-demethylase를방해하여세포막내의 ergosterol 합성을억제하여항진균효과를나타낸다. 2. 약동력학 Voriconazole 은경구용과주사용제재가있으며주사용제재는보통 1~2시간에걸쳐주입하는데부하용량으로 6 mg/kg를 12시간간격으로 2회투여후유지용량으로 4 mg/kg 용량을 12시간간격으로투여한다. 경구용제제는 50 mg과 200 mg tablet의두가지가있고보통체중 40 kg 이상의성인에서는첫날에는 400 mg 씩, 이후 200 mg 씩을 12시간마다복용한다. 복용후 1~2시간내에혈장최고농도에도달하고공복시의위장관흡수율이 90% 를넘는다. 혈장반감기는약 6시간정도이고혈중단백결합율은 58% 이며대부분간에서의 CYP450 효소군에의해서대사된후소변으로배출된다. Voriconazole은 CSF의농도가혈장농도의 50% 정도가되고뇌조직에서의농도는 CSF에서의농도보다더높다. 간에서의대사물은항진균효과가없고간질환환자에서는부하용량은그대로유지하되유지용량의감량이필요하다. 중증간질환환자에서의안전성은증명되지않았고, 크레아티닌청소율이 50 ml/min 이하일시에는주사용제제에들어있는 sulfobutyl ether β-cyclodextrin sodium (SBECD) 라는부형제가축적되므로주사용제재의사용을피하는것이좋지만경구용제재는용량조절없이사용이가능하다. 3. 부작용및약물상호작용간기능이상 (10~20%), 발진 (<10%), 환시 (<10%), 시각장애 (25~45%) 등의 4가지부작용이가장흔하다. 시각장애는보통투여후 15~30분사이에발생하며일시적이고용량과의연관관계가있으며주로광과민증, 흐린시력 (blurred vision) 으로나타나고망막의구조적손상은증명되지않았다. 대부분의임상실험에서복용을중단해야할만큼의심각한부작용은 2~13% 로드물었다 20,21. Voriconazole은 cytochrome P-450 유도체인 rifampin, barbiturate, carbamazepine 등에의해혈장농도가떨어지고 rifabutin, phenytoin 등과같이사용시에는 voriconazole의농도가떨어질뿐만아니라 rifabutin, phenytoin의농도도올라가서같이투여하는것을피하는것이좋다. 또 warfarin, quinidine, cyclosporine, sirolimus, tacrolimus, astemizole, cisapride의대사를방해하여혈장농도를독성농도 (toxic level) 까지올릴수있으므로이런약들의용량은감량이필요하고 warfarine 투여시 prothrombin time 같은혈장농도지표들의주의깊은감시를요한다. 4. 항진균작용 Voriconazole 은제 2세대 triazole 중에서처음으로개발된약으로서대부분의효모균과사상균에대한광범위한항진균력을갖는다. 효모균보다사상균의 lanosterol 14-α-demethylase에대해강한결합력을가지고있어일부사상균에대해서는살균작용 (fungicidal) 을보이나효모균에대해서는보통정균작용 (fungistatic) 을보인다 22. Voriconazole 은 fluconazole에본태성내성을가진 C. krusei와획득내성을가진 C. glabrata를포함한모든 Candida에효과가있고 Cryptococcus neoformans, Trichosporon beigelii, Saccharomyces cerevisiae 등에대해서도좋은효과를보였다 23,24. 또 amphotericin B에종종 resistant 한 A. terreus를포함한모든 aspergillus에효과가있고 21 Blastomyces dermatitis, Coccidioides immitis, Histoplasma capsulatum, Fusarium spp, Scedosporium apiospermum 에도상당한효과가있으나 Sporothrix schenckii에는효과가떨어지고 zygomycetes에는항진균력이없다 24. 5. 임상적적용식도칸디다증을대상으로한대규모무작위대조군임상연구에서 fluconazole과 voriconazole의치료성공률이각각 95.1% 와 98.3% 로차이가없었고 25 fluconazole에반응하지않는식도칸디다증을가진 AIDS 환자들에서 voriconazole의효과가증명되었다 20. 침습적 aspergillosis를대상으로시행한대규모임상연구에서 voriconazole은 48% 의치료성공률을보였고 24, 다른대규모연구에서 amphotericin B에비해더좋은반응률과생존률의향상을보였다 21. 침습적 aspergillosis의구제치료 (salvage therapy) 로사용한경우에도반응률이 41~55% 정도를보였다 - 4 -
전재범등 : 전신성항진균제와임상적이용 25,26. 이런연구들로미루어침습적 aspergillosis의치료에 voriconazole이선택약제로쓰일수있겠다. 지속되는호중구감소성발열환자에서 voriconazole과 liposomal amphotericin B를비교한연구에서반응률과생존률은비슷하였으나치료중진균감염 (breakthrough infection) 이나열, 오한등의약제부작용과신독성은 voriconazole 군에서훨씬적었다 27. 하지만이연구의결과는논란이있어서호중구감소성발열환자에서의경험적일차치료제로는 FDA의허가가나지않은상태이다. 그외소수의연구에서진균에의한 CNS 감염에서 voriconazole이효과가있을것이라는보고가있다. 이는 voriconazole이뇌척수액으로의투과가좋은것과연관지을수가있겠는데 566개의임상에서분리된 C. neoformans를대상으로시행한 in vitro 연구에서 fluconazole이나 itraconazole에비해효과가좋았다. 구제요법 (salvage therapy) 으로 voriconazole 치료를받은 cryptococcal meningitis 환자 18명중 7명 (39%) 이좋은반응을보였고반응을보이지않았던 11명의환자중 10명의환자는치료종결시점에서비교적 stable한질병 양상을보였던연구결과도있다 28. 현재미국식약청과유럽에서침습적 aspergillosis, fusariosis, scedosporiosis, 불응성칸디다증의치료제로허가를받았다. Posaconazole Posaconazole은 itraconazole 유도체로서다른제 2 세대 triazole과마찬가지로효모균과사상균에광범위한항진균력을가지고있으며 voriconazole과달리 zygomycetes 감염에 in vivo, in vitro 연구에서항진균력을나타내었다 29~31. 현재주사용제재는개발중이고경구용제재만이나와있으며하루에 200 mg 씩 4회복용하는것이추천되며고지방식이시에경구흡수율이증가하였다. Aspergillosis, fusariosis, crytococcosis, candidiasis, phaeohyphomycosis 등의침습적진균감염을대상으로한구제요법 (salvage therapy) 으로 posaconazole 200 mg qid 또는 400 mg bid로 4~8주간치료하였을때반응률이 44~80% 정도가되었다 32. 치료시에심각한부작용은보고되지않았으며가장흔했던부작용은설사, 복부팽만 (flatulence), 무력증 (asthenia), 안구통등이었다. Fig. 3. Structural formulas of echinocandin lipopeptides caspofungin, anidulafungin and micafungin. - 5 -
대한의진균학회지제 10 권제 1 호 2005 Ravuconazole Ravuconazole은경구용제재와주사용제재가모두나와있으며경구흡수율이높고 posaconazole과달리반감기가길어서하루에한번투여가가능하다. 칸디다증환자들을대상으로한연구에서 ravuconazole 400 mg/day 치료로 fluconazole 200 mg/day 치료와비슷한치료성공률 (86% vs 78%) 을보였고심각한부작용은발생하지않았다. 건강한성인을대상으로한연구에서 800 mg/day 용량으로 2주간복용했을때도특별한부작용이관찰되지는않았다 32. Echinocandins: caspofungin, micafungin, anidulafungin Caspofungin 1. 구조및작용기전 Echinocandin계항진균제는고분자반합성 lipopeptide로서 caspofungin micafungin anidulafungin 등으로나눌수있으며이들은모두 cyclic hexapeptide에여러종류의 lipid side chain들이붙어있는모양을 하고있다 (Fig. 3). 이들은진균세포벽의주성분인 1,3-β-glucan 합성에중요한역할을하는 1,3-β-glucan synthase를비경쟁적으로억제하여살진균작용을나타낸다 33 (Fig. 4). 사람의몸에는세포벽이없기때문에부작용이적고진균에선택적인효과를나타낼수있다. 이렇게이전의항진균제와는다른작용기전으로살진균효과를내기때문에향후다른항진균제와의병용치료 (combination therapy) 로사용될가능성이높다. 2. 약동력학 Caspofungin은경구흡수율이떨어져서주사용제재만이사용되고혈장반감기가 10~15시간정도로하루에한번투여가가능하다. 단백결합율이 95% 정도로뇌를비롯한주요장기에잘분포하지만염증이없는뇌척수액에의투과도는낮다. Echinocandin 계항진균제는 cytochrome P450 효소를억제하지않고간에서대사되어천천히소변과대변으로배설된다. 신부전시에용량조절은필요치않고간부전시에는감량이필요하다. 성인에서부하용량 70 mg/ day을투여하고유지용량으로 50 mg/day를투여하는것이추천된다. Fig. 4. Schematic of the proposed mechanism of action of echinocandin lipopeptides. Echinocandins inhibits the synthesis of cell wall 1,3-β-glucan at the level of cell membrane (Fks = proposed catalytic subunit; Rho = proposed regulatory subunit of the glucan synthase complex) - 6 -
전재범등 : 전신성항진균제와임상적이용 3. 부작용및약물상호작용 Echinocandin계항진균제의가장흔한부작용은간기능이상, 두통, 복부불편감등이며그외히스타민분비와관련된증상과발진등이 5% 미만으로있었고발열이 micafungin에서는드물었지만 caspofungin 치료시에는 35% 까지보고되었다. 대체로임상연구중부작용으로복용을중단했던경우는 5% 미만이었다 34. Phenytoin, carbamazepine, efavirenz, nevirapine, rifampin, dexamethasone 투여환자에서 caspofungin의 AUC가 20% 정도감소되기때문에이런약들을투여하는환자에서는유지용량을 70 mg/day로증량하여야한다. Caspofungin은 amphotericin B와 itraconazole 등과는상호작용이없고 tacrolimus의혈중농도를약 20% 감소시키나 cyclosporine 의농도에는영향이없다. 하지만 cyclosporine은 caspofungin의 AUC를약 35% 정도올리므로같이사용하는것은피하는것이좋다. 4. 항진균작용 Echinocandin계항진균제의사용은주로 Candida spp와 Aspergillus spp에국한되고 Cryptococcus, Trichosporon spp, zygomycetes, Fusarium spp 등에의한감염에서의사용은제한적이다. 동물실험에서 Pneumocystis carinii 감염에도효과가있는것이확인되었다 35. In vitro 연구들에서보면 3가지약모두 fluconazole resistant한 Candida를포함한 Candida spp 들에대해살균작용 (fungicidal) 효과를보였으며 amphotericin B, fluconazole 등과비교하였을때 Candida parasilosis와 Candida guilliermondii에서는비슷한 MIC를보였으나그외의다른 Candida spp에대해서는훨씬낮은 MIC를보였다 36,37. Caspofungin의경우에는 in vitro 연구에서다른 Candida spp에비해 C. parasilosis, C. lusitaniae, C. guilliermondii에서는효과가약간떨어지는것이관찰되었고 38 균막 (biofilm) 의파괴효과가관찰되었다 39. 동물실험에서 Aspergillus에대해서는정균작용 (fungistatic) 을보였으며 3가지약모두침습적 aspergillosis에서 amphotericin B, itraconazole에비해생존률에향상이있었다 40. 다른 azole계나 polyene계항진균제와의교차내성은관찰되지않았고이것은아마도 echinocandin 의작용기전이다른것때문으로생각된다. 5. 임상적적용식도칸디다증을대상으로한임상연구에서 caspofungin의 35 mg/day, 50 mg/day, 70 mg/day 치료군에서치료성공률이각각 67%, 90%, 77% 로 amphotericin B의치료성공률 (61%) 에비해높았고 41 fluconazole 치료에실패한식도칸디다증 AIDS 환자에서도좋은효과를보였다 42. 전신성칸디다증을대상으로 caspofungin과 amphotericin B를비교한임상시험에서치료성공률이각각 73% 와 62% 로 caspofungin군에서더높았고부작용도적었다 43. 이런연구들을근거로 caspofungin은전신성칸디다증의치료에미국식약청의승인을받았다. Crytoococcosis에서의임상연구결과는거의없다. 적절한항진균제로 7일이상치료했음에도불구하고반응이없거나약물부작용등으로치료를중단했던침습적 aspergillosis 환자 56명을대상으로 45% 의치료성공률을보인임상연구등을근거로침습적 aspergillosis의구제요법 (salvage therapy) 로미국식약청의승인을받았다 44. 이연구는최근에환자수를추가하여총 90명의환자들을분석한결과를발표하였는데 caspofungin을 7일이상치료받은환자군에서의치료성공률이 56% 까지향상된결과를보였다. Caspofungin 은다른항진균제와복합요법으로많이사용될것이기대되는약으로소수의백혈병환자들을대상으로한연구들에서 amphotericin B 치료에실패한침습적 aspergillosis 환자군에서 caspofungin을추가하거나 caspofungin과 voriconazole의복합요법을시행하였을때 60% 이상의치료성공률이관찰되었고심각한약제부작용은관찰되지않았다 44. Micafungin Micafungin은 caspofungin과마찬가지로경구흡수율이낮아주사용제재만이개발되어있으며약동력학, 항진균범위등도 caspofungin과유사하다 45. 다른 echinocandins이나 azoles 등과의병용치료 (combination therapy) 의유용성이 in vivo와 in vitro 연구에서관찰되었다 46,47. 임상연구결과들을보면 50~100 mg/day 용량으로투여하였을때전신성 aspergillosis와 candidiasis에서치료성공률이높았다. 골 - 7 -
대한의진균학회지제 10 권제 1 호 2005 수이식환자들을대상으로한대규모임상연구에서예방적으로 micafungin을하루 50 mg 투여한군과 fluconazole을하루 400 mg을투여한군의진균감염률이 micafungin 군에서유의하게낮게나왔다 32. 임상연구에서관찰된부작용으로는오심, 구토, 간기능이상이가장많았고 caspofungin에서보이는히스타민분비관련증상은보이지않았고 cyclosporin 과의약물상호작용도관찰되지않았다. 이런결과들로골수이식환자들에서의예방적요법으로는 50 mg/day, candida나 aspergillus에의한전신성진균감염에서는 100~150 mg/day 정도의용량이필요할것으로생각된다. Anidulafungin Anidulafungin도역시주사용제재만이사용이가능하고약동력학항진균범위등이 caspofungin이나 micafungin과큰차이가없다. 식도칸디다증에서 anidulafungin과 fluconazole을비교한임상연구에서치료성공률이각각 97.2% 와 98.8% 로차이가없었고부작용도두군간에차이가없었다. 임상연구결과가많지않아적절한치료용량을알기는어려우나칸디다혈증을대상으로한임상연구에서보면부하용량을 100 mg/day 사용후유지용량을 50 mg/ day로사용한군과, 부하용량을 150 mg/day 사용후유지용량을 75 mg/day로사용한군, 부하용량을 200 mg/day 사용후유지용량을 100 mg/day로사용한군에서치료성공률은 83~92% 정도로세군간에의미있는차이는없었고심각한약제부작용도관찰되지않았다 32. 요약전신성진균감염에대하여개발된항진균제로이미기술된 fluconazole, itraconazole을제외한 amphotericin B lipid formulation 인 AmB colloidal dispersion ([ABCD] Amphocil or Amphotec), AmB lipid complex ([ABLC] Abelcet), a small unilamellar vesicle liposomal formulation ([L-AmB] AmBisome) 과 triazole계의 voriconazole, ravuconazole, posaconazole 그리고 echinocandin계의 caspofungin, micafungin, anidulafungin의약리학적특성과임상적응증에대하여간략히정리 하였다. 참고문헌 1. 우준희. 항바이러스약제와항진균제. 대한의학협회지 1989; 32: 615-22 2. 정희영. 전신성진균감염증의항균요법. 대한내과학회잡지 1974; 17: 414-417 3. 우준희. 정두련, 류지소. 전신적항진균제. 의진균지 1997; 2: 110-122 4. 조용균. 새로운항진균제. 의진균지 2003; 8: 147-56 5. Plempel M, Buchel KH, Bartmann K, Regel E. Antimycotic properties of clotrimazole. Postgrad Med J 1974; 50: 11-12 6. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrob Agents Chemother 1988; 32: 1-8 7. Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002; 2: 73-85 8. New RR, Chance ML, Heath S. Antileishmanial activity of amphotericin and other antifungal agents entrapped in liposomes. J Antimicrob Chemother. 1981; 8: 371-381. 9. Graybill JR, Craven PC, Taylor RL, Williams DM, Magee WE. Treatment of murine cryptococcosis with liposome-associated amphotericin B. J Infect Dis 1982; 145: 748-752. 10. Taylor RL, Williams DM, Craven PC, et al. Amphotericin B in liposomes: a novel therapy for histoplasmosis. Am Rev Respir Dis 1982; 125: 610-611 11. Bolard J. How do the polyene macrolide antibiotics affect the cellular membrane properties?. Biochim Biophys Acta 1986; 864: 257-304 12. Brajtburg J, Elberg S, Schwartz DR, et al. Involvement of oxidative damage in erythrocyte lysis induced by amphotericin B. Antimicrob Agents Chemother 1985; 27: 172-176 13. Fielding RM. Liposomal drug delivery. Advantages and limitations from a clinical pharmacokinetic and - 8 -
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