Semis Rita, Nili Shai Shmuel, Munitz Ariel, Zaslavsky Zeev, Polacheck Itzhack, Segal Esther
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
J Antimicrob Chemother. 2012 Jul;67(7):1716-21. doi: 10.1093/jac/dks117. Epub 2012 Apr 11.
We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice.
Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay.
Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those elicited by nystatin.
Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses.
我们开发了一种适用于肠胃外给药的新型制霉菌素脂质制剂——制霉菌素-脂质乳剂（NYT-IL），其在小鼠体内具有抗真菌活性且毒性降低。我们研究了NYT-IL在小鼠体内的药代动力学、组织分布及免疫调节作用。
在小鼠中给予NYT-IL或制霉菌素后，使用高效液相色谱法测定血清和器官中的制霉菌素水平。通过酶联免疫吸附测定法评估注射NYT-IL或制霉菌素的小鼠脾细胞产生的促炎细胞因子肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）以及抗炎细胞因子白细胞介素10（IL-10）的水平。
与注射制霉菌素相比，注射NYT-IL导致血清中制霉菌素水平和动力学相似，肝脏中浓度较高，肾脏中浓度较低。给小鼠注射NYT-IL产生的IL-10水平高于制霉菌素，而NYT-IL诱导的TNF-α和IFN-γ水平低于制霉菌素诱导的水平。
由于多烯治疗与肾毒性相关，NYT-IL注射后肾脏中制霉菌素水平较低表明毒性降低的可能性。由于多烯治疗相关的急性输注相关不良反应被认为是由促炎细胞因子诱导的，NYT-IL给药引发的较高水平抗炎细胞因子和较低水平促炎细胞因子表明有改善此类效应的可能性。总之，由于使用这种制霉菌素脂质制剂而导致的药代动力学、组织分布和免疫反应的改变，值得进一步研究以开发一种针对侵袭性真菌病的治疗药物。
