Lipid emulsion reduces subacute toxicity of amphotericin B: a histopathological study.
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.
Souza
L C
LC
Departamento de Análises Clinicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, SP, Brazil.
Saldiva
P H
PH
Campa
A
A
D000666:Amphotericin B / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003840:Deoxycholic Acid / Q000008:administration & dosage; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000008:administration & dosage
D000935:Antifungal Agents; D005217:Fat Emulsions, Intravenous; D014280:Triglycerides; D003840:Deoxycholic Acid; D000666:Amphotericin B