Nanomedicine Research and Education Center, Semmelweis University, Budapest, Hungary.
Adv Drug Deliv Rev. 2012 Dec;64(15):1706-16. doi: 10.1016/j.addr.2012.07.005. Epub 2012 Jul 20.
Intravenous administration of low (milligram) doses of nanoparticulate materials in pigs can lead to acute cardiopulmonary, hemodynamic, hematological, biochemical and dermatological changes within minutes, mimicking the human infusion (or anaphylactoid) reactions to many state-of-the-art (nano)medicines and biologicals. Because of the causal role of complement (C) activation, the phenomenon was called C activation-related pseudoallergy (CARPA). This review summarizes the available information on porcine CARPA caused by different liposomes and polymers. It provides methodical details of the model and addresses the quantitation, sensitivity, specificity, reproducibility and variability of symptoms caused by different reactogenic drugs. We describe a unique feature of the model: the rise of tachyphylaxis (self-induced tolerance) as a function of structural properties of reactogenic agents. For drugs that cause tachyphylactic CARPA, such as liposomal doxorubicin (Doxil), the review recapitulates a recently reported method of desensitization, which may prevent this, as well as many similar hypersensitivity reactions. In explaining the underlying mechanism of tachyphylactic CARPA, a new theory on "double hit" is outlined, wherein the pulmonary intravascular macrophages (PIM cells) of pigs give aggravated response to simultaneous stimulation of their anaphylatoxin and other surface receptors (e.g., toll-like, PAMP, DAMP or mannose) that recognize vesicle surface molecular patterns. The porcine CARPA model might provide unique advantages in studying the mechanism of severe hypersensitivity reactions in man to i.v. drugs, as well as in identifying drugs and drug carriers that may cause such reactions.
静脉内给予低（毫克）剂量的纳米颗粒材料可在数分钟内导致猪出现急性心肺、血液动力学、血液学、生化和皮肤变化，模拟人类对许多最先进的（纳米）药物和生物制剂的输注（或过敏样）反应。由于补体（C）激活的因果作用，这种现象被称为 C 激活相关假性过敏（CARPA）。本综述总结了不同脂质体和聚合物引起的猪 CARPA 的现有信息。它提供了该模型的方法学细节，并解决了不同反应性药物引起的症状的定量、敏感性、特异性、重现性和可变性。我们描述了该模型的一个独特特征：作为反应性药物结构特性的函数，心动过速（自身诱导的耐受性）的上升。对于引起心动过速 CARPA 的药物，如脂质体阿霉素（Doxil），综述回顾了最近报道的脱敏方法，该方法可能预防这种情况以及许多类似的过敏反应。在解释心动过速 CARPA 的潜在机制时，概述了一种关于“双重打击”的新理论，其中猪的肺血管内巨噬细胞（PIM 细胞）对其过敏毒素和其他表面受体（例如，toll 样、PAMP、DAMP 或甘露糖）的同时刺激产生加重的反应，这些受体识别囊泡表面的分子模式。猪 CARPA 模型可能在研究人类对静脉内药物的严重过敏反应的机制以及识别可能引起此类反应的药物和药物载体方面提供独特的优势。
