Gulati M, Bajad S, Singh S, Ferdous A J, Singh M
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
J Microencapsul. 1998 Mar-Apr;15(2):137-51. doi: 10.3109/02652049809006844.
A considerable effort has been spent in the past three decades to investigate various aspects of liposomes as novel drug delivery systems. In 1990, the first amphotericin B (AmB) liposomal preparation (L-AmB) under the brand name AmBisome was introduced into the market by Vestar. The successful marketing of the product moved liposomes out of the stage of experimental obscurity to the realistic stage of clinical utility. The launch of AmBisome sparked off the introduction of other lipid-based AmB products marketed by Liposome Technology (Amphocil) and The Liposome Co. (Abelcet). The drive behind the development of a modified formulation of AmB was to improve the therapeutic index of this drug with respect to its major drawback associated with both acute and chronic toxic effects. In a 30-year-long experience with AmB, several reports were recorded in the literature of acute adverse effects, such as fever, rigors, vomiting, cardiotoxicity and hypotension occurring during infusion; while long-term therapy was reported to be associated with hypokalemia, renal dysfunction and hematological abnormalities. Another serious problem encountered with the drug had been the poor response obtained in immunocompromised patients like those with AIDS, neutropenia and cancer patients on chemotherapy. The encapsulation of amphotericin B in liposomal vesicles was hence targeted not only to obtain an improvement in the therapeutic index but also to see if it was useful in eradicating deep-seated fungal infections in immunocompromised patients. The liposomal AmB was found to have a better therapeutic index and lower toxicity than the commercial AmB preparations. The LD50 of AmBisome in mouse was 175 mg/kg compared with 3.7 mg/kg for Fungizone, the commercial preparation of AmB. Additionally, L-AmB has prolonged circulation time, and extravasates into the site of infection and delivers the drug directly to the site, with no nephrotoxicity and neurotoxicity as experienced with AmB. This review traces the course of development of L-AmB and discusses the rationale behind the development of its liposomal preparation. The results in in vitro, in vivo and clinical studies, mechanism of action, biodistribution, and formulation considerations of L-AmB are described. The clinical experience with the marketed preparation is reviewed.
在过去三十年里，人们付出了巨大努力来研究脂质体作为新型药物递送系统的各个方面。1990年，首个两性霉素B（AmB）脂质体制剂（L-AmB）以安必素（AmBisome）的品牌名由Vestar公司推向市场。该产品的成功上市使脂质体从实验性的默默无闻阶段进入了临床应用的实际阶段。安必素的推出引发了其他由脂质体技术公司（两性霉素B脂质体注射剂（Amphocil））和脂质体公司（阿贝西普（Abelcet））销售的基于脂质的AmB产品的推出。开发AmB改良制剂背后的驱动力是提高该药物的治疗指数，以解决其与急慢性毒性相关的主要缺点。在使用AmB的30年经验中，文献记录了几例急性不良反应，如输液期间出现的发热、寒战、呕吐、心脏毒性和低血压；而长期治疗据报道与低钾血症、肾功能不全和血液学异常有关。该药物遇到的另一个严重问题是在免疫功能低下的患者（如艾滋病患者、中性粒细胞减少症患者和接受化疗的癌症患者）中疗效不佳。因此，将两性霉素B包裹在脂质体囊泡中的目的不仅是提高治疗指数，还在于观察其是否有助于根除免疫功能低下患者的深部真菌感染。结果发现，脂质体AmB比市售的AmB制剂具有更好的治疗指数和更低的毒性。安必素在小鼠中的半数致死量（LD50）为175毫克/千克，而AmB的市售制剂两性霉素B注射剂（Fungizone）为3.7毫克/千克。此外，L-AmB的循环时间延长，可渗出到感染部位并将药物直接递送至该部位，且没有两性霉素B所具有的肾毒性和神经毒性。本综述追溯了L-AmB的发展历程，并讨论了其脂质体制剂开发背后的基本原理。描述了L-AmB在体外、体内和临床研究中的结果、作用机制、生物分布和制剂考虑因素。对市售制剂的临床经验进行了综述。
