Souza L C, Saldiva P H, Campa A
Departamento de Análises Clinicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil.
Exp Toxicol Pathol. 2000 May;52(2):169-75. doi: 10.1016/S0940-2993(00)80115-3.
In previous work acute toxic effects of amphotericin B (AB) were reduced in both in vitro and in vivo tests when AB was associated with a triglyceride-rich emulsion (AB-emulsion). The present paper compares the severity of the histopathological alterations as determined by morphometry produced in the target tissues (kidneys, liver, and lungs) by AB-emulsion with those produced by the conventional formulation AB-deoxycholate (DOC) following subacute AB treatment. No morphological alterations were seen in the spleen and heart following both AB-DOC and AB-emulsion treatment. Although the alterations in the liver, kidneys and lungs are basically the same for both formulations, the intensity of the changes varies considerably. AB-emulsion always caused statistically decreased severity of morphologic alterations, compared to AB-DOC by stereological measurements, for the three treatment regimes of AB-administration. These three treatment regimens consisted of 1 mg AB/kg of body weight every 48 hours for 20 days, 2 mg AB/kg of body weight every 48 hours for 12 days, and 2 mg AB/kg of body weight for 4 consecutive days. Thus, these regimens consisted of total doses varying from 8-12 mg/kg of body weight. Specifically, these morphological changes included proximal and distal tubular edema, inflammation and tubular cell degeneration in the kidney and a moderate inflammation of the portal region in the liver. Vacuolization of hepatocytes only occurred for AB-DOC treatment. In addition, acute interstitial inflammation was observed in the lungs prior to interstitial and alveolar edema. The intensity of the histopathological damage increase with the dose and with the reduction in the time interval between AB administrations. Abnormal serum biochemical parameters were observed for serum urea which was higher for both treated AB-groups, as compared to control, and for iron which was lower for the AB-DOC group. In conclusion, the decreased severity of the morphological alterations in the kidneys, liver, and lungs following subacute treatment with AB-emulsion, as compared to AB-DOC formulation, confirms our previous results consisting of acute toxic effects induced by in vitro and in vivo tests with AB-emulsion treatment.
在之前的研究中，两性霉素B（AB）与富含甘油三酯的乳剂（AB-乳剂）联合使用时，其在体外和体内试验中的急性毒性作用均有所降低。本文比较了亚急性AB治疗后，AB-乳剂与传统制剂AB-脱氧胆酸盐（DOC）在靶组织（肾脏、肝脏和肺）中产生的组织病理学改变的严重程度，这些改变通过形态计量学确定。AB-DOC和AB-乳剂治疗后，脾脏和心脏均未出现形态学改变。尽管两种制剂在肝脏、肾脏和肺中的改变基本相同，但改变的强度差异很大。通过体视学测量，对于AB给药的三种治疗方案，与AB-DOC相比，AB-乳剂总是导致形态学改变的严重程度在统计学上降低。这三种治疗方案包括：每48小时给予1mg AB/kg体重，共20天；每48小时给予2mg AB/kg体重，共12天；连续4天给予2mg AB/kg体重。因此，这些方案的总剂量为8-12mg/kg体重。具体而言，这些形态学改变包括肾脏近端和远端肾小管水肿、炎症以及肾小管细胞变性，肝脏门区中度炎症。仅AB-DOC治疗出现肝细胞空泡化。此外，在间质和肺泡水肿之前，肺部观察到急性间质炎症。组织病理学损伤的强度随剂量增加以及AB给药间隔时间缩短而增加。血清生化参数异常表现为：与对照组相比，两个AB治疗组的血清尿素均较高，AB-DOC组的铁较低。总之，与AB-DOC制剂相比，亚急性AB-乳剂治疗后肾脏、肝脏和肺中形态学改变的严重程度降低，证实了我们之前关于AB-乳剂治疗在体外和体内试验中诱导急性毒性作用的结果。
