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ABSTRACT: The hepatotoxicity of a new erythromycin derivative, erythromycin acistrate (EA, 2'-acetyl erythromycin stearate), was compared with that of erythromycin stearate (ES), erythromycin estolate (EE) and erythromycin-11,12 cyclic carbonate (EC) in 4-5-day, 28-day and 6-month oral toxicity studies in rats and dogs. In the 4-day rat study, EC caused fatty metamorphosis in the liver. ES caused similar, but milder changes at a dose nearly five times higher. The 5-day dog study revealed markedly increased serum alanine aminotransferase (S-ALAT), serum aspartate aminotransferase (S-ASAT), serum alkaline phosphatase (S-APHOS) and serum gamma-glutamyl transpeptidase (S-gamma-GT) values in the EC- and EE-groups, and slightly elevated S-ALAT values also in the EA- and ES-groups. Microscopy revealed cholangitis, pericholangitis and phlebitis in the portal areas in the EC-group at all doses. Epithelial hyperplasia was observed also in the bile ducts. EE caused similar but milder changes. The changes in the EA-group were small, but mildly atypical bile duct epithelium was seen in female dogs receiving 2 x 200 mg/kg of EA. The ES-group was practically without changes and very much like the EA-group. Thus the dog proved to be a more sensitive model for assessing the hepatotoxicity of erythromycin derivatives. In the 28-day studies, only EA and ES were investigated. In the rat study, slightly elevated serum enzyme levels within the normal range were measured in the high-dose regimens of both drugs. In the dog study, 300 mg/kg of EA caused slightly elevated S-ALAT in males, but the values returned to normal after a 2-week off-dose period. Only EA was studied in the 6-month study. In male rats, 400 mg/kg of EA caused slightly elevated enzyme levels and neutral fat droplets in centrilobular hepatocytes. In male dogs given 150 mg/kg of EA, S-ALAT, S-APHOS, and S-gamma-GT values were elevated after four weeks of treatment but returned to normal thereafter. No severe changes were seen in the liver histopathology. In conclusion, EC and EE were clearly hepatotoxic in dogs, and EC also in rats. EA, and to a somewhat lesser extent ES, showed signs of mild hepatotoxicity only at high doses. This evidently reversible effect was considered a common characteristic of erythromycins.
Journal of Antimicrobial Chemotherapy 07/1988; 21 Suppl D:9-27. · 5.07 Impact Factor
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ABSTRACT: Continuous topical administration of dithranol and butantrone for 6 months caused different irritation profiles in miniature swine. In paraffin wax sticks in white petrolatum, butantrone gave rise to much less initial irritation than dithranol, but after 2-3 weeks the situation had equalized. In gel formulations, butantrone was initially more irritant than dithranol. The vehicles themselves induced significant irritation. Signs of skin hyperplasia (parakeratosis and acanthosis) and inflammation were frequent histopathological findings at the end of the study, but no malignant changes were found. Dithranol and butantrone did not produce any chemical, hematological or serious histological abnormalities during the treatment, suggesting a lack of systemic toxicity. No evidence of systemic absorption was found. This long-term study did not predict delayed irritation of butantrone observed in about 1/3 of the psoriatic patients after treatment for 1-2 months.
Contact Dermatitis 08/1986; 15(1):1-9. · 3.51 Impact Factor
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ABSTRACT: The tumor-producing activity of local applications of dithranol, 10-propionyl dithranol and butantrone was studied in 420 female white NMRI mice. An initiation with 20 micrograms of 7,12-dimethyl-benz(alpha)anthracene (DMBA) was followed 2 weeks later by three applications per week of the test compounds in 50 microliters of acetone for 50 weeks. Several control groups receiving only acetone or DMBA and test compounds without DMBA were included. Dithranol and 10-propionyl dithranol caused transient, although serious, skin irritation during the first 2 weeks of the treatment. Hyperplasia was a common finding in the same groups at the end of the treatment. Dithranol (3.5 mM) induced 11 papillomas in 8 mice (26.7%) without DMBA and 29 papillomas in 17 mice (56.7%) with DMBA. 10-Propionyl dithranol was tumorigenic as well: 3.5 mM caused 15 papillomas in 11 mice (36.6%) without DMBA and 28 papillomas in 17 mice (56.7%) with DMBA and 1.5 mM with DMBA caused 7 papillomas in 6 mice (20%). In the butantrone groups, there was only one single papilloma with the 1.5 mM concentration plus DMBA. It is concluded that, in contrast to dithranol and 10-propionyl dithranol, butantrone (3.5 mM) is not tumorigenic in the dorsal murine skin.
Journal of Pharmacology and Experimental Therapeutics 05/1984; 229(1):255-60. · 3.83 Impact Factor
