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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Experimental central nervous system aspergillosis therapy: Efficacy, drug levels and localization, immunohistopathology, and toxicity
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Experimental central nervous system aspergillosis therapy: Efficacy, drug levels and localization, immunohistopathology, and toxicity

机译：实验性中枢神经系统曲霉病治疗：功效，药物水平和定位，免疫组织病理学和毒性

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We have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice given Aspergillus fumigatus conidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.
机译：以前我们已经表明，高剂量的脂质两性霉素制剂在曲霉病中并不比低剂量更有效。我们使用4天的中枢神经系统（CNS）曲霉病模型评估了早期事件，同时研究了毒性，药物浓度和定位以及定量感染。脑内给予烟曲霉分生孢子的小鼠，在环磷酰胺免疫抑制方案下治疗3天（AmBisome的体重为3或10 mg / kg，Abelcet的剂量为10 mg / kg，两性霉素B的脱氧胆酸盐B的剂量为1 mg / kg，卡泊芬净的剂量为5毫克/公斤或伏立康唑40毫克/公斤）。最后一次治疗后24小时取样显示，AmBisome的浓度为3，但不是10 mg / kg，Abelcet，卡泊芬净和伏立康唑的浓度却降低了脑CFU。所有方案均减少了肾脏感染。 AmBisome或Abelcet治疗可引起轻微的肾小管改变，而心，肺和脑则无药物毒性。两性霉素B组织和血清浓度与疗效无关。感染期间发生内皮细胞激活（脑毛细血管中的ICAM-1和P-选择素）。来自AmBisome和Abelcet的两性霉素B位于活化的内皮中，而来自Abelcet的血管内单核细胞。在为期10天的未感染小鼠用药研究中，AmBisome或Abelcet剂量为1、5或10 mg / kg或未使用环磷酰胺治疗后，肾小管发生了轻微变化。在环磷酰胺治疗的小鼠中，只有Abelcet发生肾病。肝毒性发生在AmBisome和Abelcet上，但在环磷酰胺治疗的小鼠中降低了。 AmBisome以3 mg / kg的剂量将CFU明显降低，这与相对更强烈的炎症有关。 Abelcet肾定位似乎是晚期肾毒性的先兆。肝毒性可能导致大剂量的Abelcet和AmBisome衰竭。我们在感染过程中内皮两性霉素定位的新颖观察可能有助于两性霉素的功效机制。

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