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Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat
J A Turton1, D Yallop, C M Andrews
1Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Abstract:
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.
Insights
Chloramphenicol succinate (CAPS) causes reversible anemia in mice, mirroring human responses. This study investigated CAPS
Area of Science:
- Toxicology
- Hematology
- Pharmacology
Background:
- Chloramphenicol is a vital antibiotic for serious infections.
- It is known to cause dose-dependent, reversible anemia and potentially fatal aplastic anemia or leukemia in humans.
- Understanding its hematotoxicity is crucial for safe clinical use.
Purpose of the Study:
- To investigate the hematotoxicity of chloramphenicol succinate (CAPS) in CD-1 mice.
- To compare the hematological response in mice to that observed in humans.
- To assess CAPS's effects in Wistar Hanover rats.
Main Methods:
- Repeat dose oral gavage studies of CAPS in female CD-1 mice and male Wistar Hanover rats.
- Hematological parameters (RBC, HCT, Hb, reticulocytes, platelets, WBC) were analyzed.
- Apoptosis in bone marrow mononuclear cells and serum biochemistry were evaluated.
Main Results:
- In mice, CAPS significantly reduced reticulocytes, erythrocytes (RBC), hematocrit (HCT), and hemoglobin (Hb) at high doses.
- These hematological changes in mice were reversible, returning to normal levels within 15 days post-dosing.
- Increased apoptosis in bone marrow cells was observed in mice but not in rats; rats showed reduced Hb at high doses.
Conclusions:
- CAPS administration in mice induced hematological changes that closely parallel reversible chloramphenicol-induced anemia in humans.
- The findings suggest that CD-1 mice are a suitable model for studying chloramphenicol's reversible hematotoxicity.
- Further research may elucidate species-specific mechanisms of chloramphenicol-induced hematotoxicity.
