title: Studies on the haemotoxicity of chloramphenicol succinate in the Dunkin Hartley guinea pig.
abstract: In man, chloramphenicol (CAP), induces two major haemotoxic effects. First, a reversible, dose-related reticulocytopenia and anaemia developing during treatment. Second, a non-dose-related aplastic anaemia (AA), developing weeks after treatment, is often irreversible and fatal. In previous studies, we developed a mouse model of the reversible reticulocytopenia/anaemia using CAP succinate (CAPS); attempts to induce AA in the mouse with CAPS were unsuccessful; in the rat, CAPS induced only minimal haemotoxicity. We therefore wished to investigate haematological changes caused by CAPS in a third rodent, particularly in relation to the induction of significant 'late stage' bone marrow depression (AA). Female guinea pigs were gavaged with CAPS in three experiments. In a dose ranging study, CAPS (at 2500 and 3500 mg/kg) was administered daily for 9 days, and blood examined at 1 day post dosing. CAPS induced increased erythrocyte values (an apparent haemoconcentration effect), and reduced reticulocytes and femoral marrow nucleated cell counts (FNCC). In a second experiment, CAPS was given at 333, 666 and 1000 mg/kg (13 days); haematological changes were compared with results from the initial study, with evidence of dose-related effects. In a final experiment, CAPS was administered (825 mg/kg, 16 days) and blood studied at 1, 12, 28 and 63 days post dosing. At day 1, erythrocyte values were decreased (NS), and reticulocytes and FNCC were reduced; the marrow was hypocellular with erythroid depletion. At 12 and 28 days, values returned towards the normal range. At 63 days, parameters were normal. Thus, CAPS (825 mg/kg for 16 days) induced changes comparable to the reversible bone marrow depression seen in man; but there was no evidence of 'late stage' (i.e. at 63 days) marrow depression, as would be seen in a developing or overt marrow aplasia (AA). The guinea pig (like the mouse) is a model for the early events, but is not a good model for CAP-induced AA in man.
authors.affiliation: Centre for Toxicology, Department of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK. john.turton@cua.ulsop.ac.uk
authors.forename: J A
authors.initials: JA
authors.lastname: Turton
authors.forename: C M
authors.initials: CM
authors.lastname: Andrews
authors.forename: A C
authors.initials: AC
authors.lastname: Havard
authors.forename: T C
authors.initials: TC
authors.lastname: Williams
mesh_terms: D000740:Anemia / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001854:Bone Marrow Cells; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D006168:Guinea Pigs; D023421:Models, Animal; D017701:Reticulocyte Count; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D002701:Chloramphenicol; C026016:chloramphenicol succinate