Circadian haematotoxicity of the antiepileptic valproic acid in mice

Antiepileptic drugs may have varying toxicity or efficacy depending on administration time. VPA administration could be associated with a great deal of haematological toxicity and can cause aplasic anaemia or peripheral cytopenia affecting one or more cell lines. The objective of this study is to experimentally verify if VPA-induced haematological toxicity in mice varies according to drug administration time in the 24 h scale. Different groups of mice received 620 mg/kg of VPA by i.p. route at four different circadian stages. The results obtained showed that VPA treatment induced a significant decrease in the haematological parameter rates (cytopenia) depending on the circadian time; otherwise the Cosinor analysis showed that each haematological variable followed a significant blood type circadian physiological rhythm in controls and in treated mice. The highest significant haematological toxicity illustrated by the leucopenia index and thrombocytopenia was observed in the middle of the dark-activity phase (19 HALO). Chronotherapy may play an important role in improving the control of seizures and limiting the adverse effects of VPA treatment. Indeed, the data obtained indicate that the optimal haematological tolerance is observed when VPA was injected in the middle of the light-rest span of mice, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.