Arning M, Kliche K O, Heer-Sonderhoff A H, Wehmeier A
Department of Haematology, Heinrich Heine University Medical Center, Düsseldorf, Germany.
Mycoses. 1995 Nov-Dec;38(11-12):459-65. doi: 10.1111/j.1439-0507.1995.tb00020.x.
A prospective study was performed to compare the infusion-associated toxicity of three different amphotericin B preparations and to correlate acute side-effects with plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1-RA) during and after the infusions. Six adult neutropenic patients with acute leukaemia suffering from suspected or documented systemic fungal infections were treated on three consecutive days with conventional amphotericin B (AmB), liposomal AmB (AmBisome) and AmB mixed in lipid emulsion (AmB/lipid). Drugs were given over 1-2 h. Drug-induced toxicity was monitored every 30 min for 4 h. Plasma levels of the three cytokines were determined using commercially available enzyme-linked immunosorbent assay (ELISA) techniques. Four of six patients showed toxicity after AmB and AmB/lipid infusions; only one patient reacted to liposomal AmB. Clinical toxicity was associated with increases in TNF-alpha plasma levels during two of four infusions of AmB and three of four infusions of AmB/lipid. Major increases in IL-6 occurred during three of four infusions of AmB and during all four AmB/lipid infusions associated with clinical toxicity. Three of four AmB infusions and all four AmB/lipid infusions accompanied by clinical toxicity were associated with major increases in IL-1-RA plasma concentrations. Liposomal AmB was better tolerated than AmB and AmB/lipid. This formulation also caused the lowest liberation of all three cytokines tested. The severity of clinical symptoms did not correlate closely with absolute cytokine plasma levels. The findings provide further evidence that expression of TNF-alpha, IL-6 and IL-1-RA plays an important role in mediating AmB-related acute toxicity in vivo.
进行了一项前瞻性研究，以比较三种不同两性霉素B制剂的输注相关毒性，并将急性副作用与输注期间及之后的肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1受体拮抗剂（IL-1-RA）血浆水平相关联。六名患有疑似或确诊系统性真菌感染的急性白血病成年中性粒细胞减少患者，连续三天分别接受常规两性霉素B（AmB）、脂质体两性霉素B（安必素）和脂质乳剂混合两性霉素B（AmB/脂质）治疗。药物在1 - 2小时内输注完毕。每30分钟监测4小时的药物诱导毒性。使用市售酶联免疫吸附测定（ELISA）技术测定三种细胞因子的血浆水平。六名患者中有四名在输注AmB和AmB/脂质后出现毒性；只有一名患者对脂质体两性霉素B有反应。临床毒性与AmB的四次输注中的两次以及AmB/脂质的四次输注中的三次期间TNF-α血浆水平升高有关。IL-6的大幅升高发生在AmB的四次输注中的三次以及与临床毒性相关的所有四次AmB/脂质输注期间。伴有临床毒性的AmB的四次输注中的三次以及所有四次AmB/脂质输注与IL-1-RA血浆浓度的大幅升高有关。脂质体两性霉素B的耐受性优于AmB和AmB/脂质。该制剂还导致所测试的所有三种细胞因子的释放量最低。临床症状的严重程度与细胞因子血浆绝对水平没有密切相关性。这些发现进一步证明TNF-α、IL-6和IL-1-RA的表达在介导体内AmB相关急性毒性中起重要作用。
