**4. Haematological toxicity of valproic acid**

Valproic acid has been shown to have some haematological toxicity. Acute toxicity is not common and the most adverse effects are nausea, vomiting, anorexia, thrombocytopenia, von Willebrand disease type 1, decreased factor XIII, abnormal platelet function, bleed‐ ing, haemolytic anaemia, leukopenia, leucocytosis, eosinophilia, thrombocytosis, pro‐ longed prothrombin and thromboplastin times, fibrinogen and hematoma (Kreuz et al 1992; Gerstner et al. 2006; Gerstner et al, 2008; Pan et al 2007; Mazaira, 2008; Chen et al. 2013). However, some of these effects may lead to adverse effects and life-threatining complica‐ tions such as bone marrow toxicity (Acharya & Bussel, 2000). Pharmacokinetics drug interaction involves a drug displacement from protein binding sites causing drug redistrib‐ ution (McQueen & Wardell, 1971). Valproic acid is commonly used in the treatment of seizures and as a mood stabilizer in the treatment of manic depression.

Our study presents interesting clinical findings. Laboratory tests confirmed macrocytic anaemia. Thrombocytes concentrations were decreased, but other biochemical measure‐ ments such as haemoglobin were within the normal range (Table1). However, Taher et al. (2009) reported an association between divalproex sodium (DVPX) therapy and total Hb level. It has been reported that in patients treated with VAP 18% experienced at least one episode of thrombocytopenia (Nasreddine &, Beydoun, 2008). However, Rahman et al. (2009) reported 26% of his patients experienced leukopenia. The haematological complica‐ tions in patients treated with VAP appear to be heterogenic depending on the period of treatment, taking other anticonvulsants, or additional medications (Hemingway et al. 1999; Antoniou et al. 2004). Valporic acid is able to alter hematopoiesis by inhibition of eryth‐ roid differentiation in the experimental K562 cell linkage (Chateauvieux et al. 2011). Ladd et al (2009) reported that an elevated level of creatinine phosphokinase is not required for a DSM-IV diagnosis of neuroleptic malignant syndrome (Ladds et al.2009). In our study creatinine phosphokinase was at levels 70 U/I compared to 82 U/l in controls. A creati‐ nine phosphokinase level of 800,000 U/l was reported for a patient who was being treated with a conventional antipsychotic (Sanai et al. 2006).


M=mean value

nature enters the CNS by crossing the blood brain barrier via passive diffusion and bidirec‐ tional carrier-mediated transport, such as an anion exchanger at the brain capillary endothe‐ lium (Perucca, 2002). VPA crosses into the brain parenchyma utilizing another set of transporters which results in higher neuronal and glial concentrations than interstitial fluid concentrations (Perucca, 2002). VPA, in addition to being an effective anticonvulsant and mood-stabilizing agent has been shown to be an effective anxiolytic (Lal et al., 1980), antidys‐ tonic and antinociceptive (Loscher, 1999), in animal studies. Clinically, VPA is effective in clinical depression (Delucchi & Calabrese, 1989), absence seizures (Coppola et al., 2004), tonicclonic seizures, complex partial seizures (Dean & Penry, 1988), and juvenile myoclonic epilepsy

Valproic acid has been shown to have some haematological toxicity. Acute toxicity is not common and the most adverse effects are nausea, vomiting, anorexia, thrombocytopenia, von Willebrand disease type 1, decreased factor XIII, abnormal platelet function, bleed‐ ing, haemolytic anaemia, leukopenia, leucocytosis, eosinophilia, thrombocytosis, pro‐ longed prothrombin and thromboplastin times, fibrinogen and hematoma (Kreuz et al 1992; Gerstner et al. 2006; Gerstner et al, 2008; Pan et al 2007; Mazaira, 2008; Chen et al. 2013). However, some of these effects may lead to adverse effects and life-threatining complica‐ tions such as bone marrow toxicity (Acharya & Bussel, 2000). Pharmacokinetics drug interaction involves a drug displacement from protein binding sites causing drug redistrib‐ ution (McQueen & Wardell, 1971). Valproic acid is commonly used in the treatment of

Our study presents interesting clinical findings. Laboratory tests confirmed macrocytic anaemia. Thrombocytes concentrations were decreased, but other biochemical measure‐ ments such as haemoglobin were within the normal range (Table1). However, Taher et al. (2009) reported an association between divalproex sodium (DVPX) therapy and total Hb level. It has been reported that in patients treated with VAP 18% experienced at least one episode of thrombocytopenia (Nasreddine &, Beydoun, 2008). However, Rahman et al. (2009) reported 26% of his patients experienced leukopenia. The haematological complica‐ tions in patients treated with VAP appear to be heterogenic depending on the period of treatment, taking other anticonvulsants, or additional medications (Hemingway et al. 1999; Antoniou et al. 2004). Valporic acid is able to alter hematopoiesis by inhibition of eryth‐ roid differentiation in the experimental K562 cell linkage (Chateauvieux et al. 2011). Ladd et al (2009) reported that an elevated level of creatinine phosphokinase is not required for a DSM-IV diagnosis of neuroleptic malignant syndrome (Ladds et al.2009). In our study creatinine phosphokinase was at levels 70 U/I compared to 82 U/l in controls. A creati‐ nine phosphokinase level of 800,000 U/l was reported for a patient who was being treated

seizures and as a mood stabilizer in the treatment of manic depression.

(Calleja et al., 2001).

**4. Haematological toxicity of valproic acid**

276 Pharmacology and Nutritional Intervention in the Treatment of Disease

with a conventional antipsychotic (Sanai et al. 2006).

M=mean value SD=standard deviation

SD=standard deviation n=number of observations n=number of observations

**Table 1.** The levels of eight clinical and six hematological markers in patients on VPA and in control
