Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat.
1. Chloramphenicol has been widely used in the treatment of serious infections including typhoid fever and meningitis. However, the drug is haemotoxic in man inducing firstly, a reversible, dose-dependent anaemia which develops during treatment, secondly, an often fatal aplastic anaemia with pancytopenia and acellular marrow, and thirdly, leukaemia. 2. We investigated the haemotoxicity of chloramphenicol succinate (CAPS) in female CD-1 mice in repeat dose studies, to compare the response with the reversible anaemia reported in man. Studies in male Wistar Hanover rats were also carried out. 3. CAPS was gavaged daily to mice at dose levels from 800 - 2000 mg/kg for seven days. Values were significantly reduced for reticulocytes at 1700 and 2000 mg/kg, and for erythrocytes (RBC), haematocrit (HCT), and haemoglobin (Hb) at 2000 mg/kg. Platelet and white blood cell (WBC) counts were unaffected. 4. Mice were dosed with CAPS at 1400 mg/kg for 10 days and sampled at 1, 4 and 15 days after the last dose. At day 1 post dosing, RBC, HCT and Hb values were significantly reduced, but returned to normal (or above normal) by day 4 or 15. 5. CAPS from 2000 - 4000 mg/kg was gavaged to rats daily for 19 days. Hb values were significantly lower at 3600 and 4000 mg/kg; reticulocytes were not reduced. WBC and platelet counts, in general, were unaffected. 6. Levels of apoptosis in marrow mononuclear cells were increased in CAPS-treated mice, but not in CAPS-treated rats. Serum biochemistry parameters, in general, showed few changes of toxicological significance. 7. We conclude that the administration of CAPS to CD-1 mice induced haematological changes showing close parallels with the chloramphenicol-induced reversible anaemia seen in man.
Turton
J A
JA
Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Yallop
D
D
Andrews
C M
CM
Fagg
R
R
York
M
M
Williams
T C
TC
D000741:Anemia, Aplastic / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001772:Blood Cell Count / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002701:Chloramphenicol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D019963:Clinical Chemistry Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006403:Hematologic Tests; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D002701:Chloramphenicol; C026016:chloramphenicol succinate