**3. Discussion and review**

The levels of CRP and potassium (K) were higher while haematocrit and contents of throm‐ bocytes and erythrocytes and the levels of sodium (Na), creatinine and haemoglobin were lower in the VPA group compared with the control group. All results of 14 clinical and haematological markers are shown in table 1. The results showed that thrombocyte and erythrocyte counts, haematocrit and the levels of sodium (Na), creatinine and hemoglobin were lower in the VPA group compared with the control group. Differences in haematocrit and thrombocyte and erythrocyte counts were statistically extremely significant so that these determinations besides assay of serum free carnitine can be used as markers to evaluate VPA toxicity. The haematological profile is the most common investigations patients undergo.

Many structural, biochemical and physiological changes take place in the brain following head trauma which in turn account for epileptogenesis (Katayama et al. 1990). For example, seizures occur in rats shortly after traumatic injury lead to increase in glutamate and aspartate levels which explain possible involvement in epileptogenesis (Nilson et al. 1994). Antiepileptic drugs affect hepatic enzyme levels in patients known to have a coexisting hepatic abnormality, those who develop symptoms of hepatic involvement while receiving AEDs, and perhaps those receiving bitherapy with high serum AED levels (Verma & Haidukewych, 1994). Rao et al. (1993) reported 72% of the AED-treated patients and 33% of the unmedicated patients showed an increase in one or several serum liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or gamma-glutamyl transferase (gamma-GT)]; particularly gamma-GT.

It has been reported that VPA may be associated with hyperammonemia and thrombocyto‐ penia, but the aetiology of valproic acid-induced thrombocytopenia has not been elucidated (Mallet et al. 2004). In patients receiving long-term VPA VPA-induced hyperammonaemic encephalopathy may occur (Lheureux et al. 2005). It is suggested that this severe side-effect may be promoted by a pre-existing carnitine deficiency or by deficiency induced by VPA (Lheureux et al. 2005). Because the onset of the clinical symptoms of VPA-associated hepato‐ toxicity, especially in patients with intellectual disability, is sudden and unpredictable, the aim of our study was to find out suitable biochemical and haematological markers to prevent this

Blood samples for assays of sodium (Na), potassium (K), aspartate aminotransferase (ASAT), alanine aminotranferase (ALAT), amylase, alkaline phosphatase, c-reactive protein (CRP), creatinine, haemoglobin, mean cell volume, haematocrit, erythrocytes, thrombocytes and leukocytes were obtained from ID patients with epilepsy and on VPA and from healthy persons of hospital staff after overnight fasting. All patients in this study used VPA as a monotherapy. Vacuette serum tubes were used to obtain serum samples and vacuette K2EDTA tubes were used to obtain haematological samples. All assays were made immediately after sampling in the same day. The whole large patient material was from Rinnekoti hospital, Espoo-Finland. Sex and age varied in the VPA and control groups. Approximately 50% from the whole patient and control material was male. The mean ages for the VPA group and the control group were 37±15 years and 50±10 years, respectively. Laboratory determinations and reagents:Serum sodium (Na), potassium (K), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), amylase, alkaline phosphatase, c-reactive protein (CRP) and creatinine were analyzed with Cobas Mira analyzer. Haemoglobin, mean cell volume (MCV), hematocrit, erythrocytes, thrombocytes and leukocytes were assayed with Sysmex KX-21N analyzer. All used reagents were reagent grade. All laboratory determinations were controlled

The levels of CRP and potassium (K) were higher while haematocrit and contents of throm‐ bocytes and erythrocytes and the levels of sodium (Na), creatinine and haemoglobin were lower in the VPA group compared with the control group. All results of 14 clinical and haematological markers are shown in table 1. The results showed that thrombocyte and erythrocyte counts, haematocrit and the levels of sodium (Na), creatinine and hemoglobin were lower in the VPA group compared with the control group. Differences in haematocrit and thrombocyte and erythrocyte counts were statistically extremely significant so that these determinations besides assay of serum free carnitine can be used as markers to evaluate VPA toxicity. The haematological profile is the most common investigations patients undergo.

with the control samples from Labquality Ltd, Helsinki, Finland.

state of illness.

**2. Case presentation**

274 Pharmacology and Nutritional Intervention in the Treatment of Disease

**3. Discussion and review**

The World Health Organisation defines anaemia as < 13 g Hb/dL for men and < 12 g Hb/dL for women (2001), accepting that women generally have lower haemoglobin concentrations than men. However, when ferritin levels (Waalen et al. 2002), is considered then the difference may be due to hormonal influences on red cell production (Shahidi, 1973), the do not support this (Waalen et al. 2002). Platelet counts have been found to be significantly higher in women (Butkiewicz et al.2006), with possible explanations of increased thrombopoietin in women being reported. Total leukocyte count showed to be significantly higher in women than men due to a highly significant difference in neutrophil count, with no significant correlation between monocytes, basophils and gender (Bain & England, 1975).

This study is in line with the earlier observations that VPA may induce thrombocytopenia (Koenig et al. 2006; Gerstner et al. 2006; Mallet et al. 2004). According to Gerstner et al. 2006 thrombocytopenia is the most common haematological adverse effect of VPA. An incidence varies from 5% to 60% (Gerstner et al. 2006; Zeller et al. 1999). It is suggested that there are two possible mechanisms inducing thrombocytopenia. First mechanism is that VPA have a direct toxic effect on bone marrow (Gertsner et al. 2006). Second mechanism is that VPA seems to induce the formation of autoantibody against platelets (Sandler et al. 1978). We found that contents of thrombocytes and erythrocytes lowered approximately 30 % and 10 %, respective‐ ly, in patients on VPA monotherapy. This observation supports the hypothesis that VPA seems to have a direct toxic effect on bone marrow (Gerstner et al. 2006).

To prevent severe hepatotoxicity in patients on long-term VPA therapy, it is important to control contents of thrombocytes and erythrocytes and to determine the level of serum free carnitine, regularly. If the level of serum free carnitine and the thrombocyte counts are lowered, addition of carnitine to long-term VPA regimen of epileptic patients may be indicated. Further investigations are needed to evaluate appropriate dosages of L-carnitine supplementation to epileptic patients on long-term VPA therapy.

Valproic acid (N-dipropylacetic acid, or 2-propylpentanoic acid) is one of the mainstays of therapy for epilepsy and bipolar mood disorders, due to its anticonvulsant and moodstabilizing effects (Blaheta & Cinatl, 2002). It is a branched short-chain fatty acid with a halflife of 9 to 16 hours. Clinically, VPA is usually administered as uncoated tablets, but may also be administered in the form of syrup, capsules and enteric-coated tablets. Ninety per cent of VPA in the blood is bound to albumin (Cramer & Mattson, 1979), and despite its hydrophilic 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 (Calleja et al., 2001).

TABLE 1. The levels of eight clinical and six hematological markers in patients on VPA and in controls

Clinical and Hematological Profiles During Valproate Treatment of Epileptic Patients with...

http://dx.doi.org/10.5772/57369

277

Determinations Patients (M±SD) (n) Controls (M±SD) (n) p-value

Thrombocytes (E9/l) 186±67 (141) 259±59 (367) 1.4×10-23 Erythrocytes (E12/l) 4.1±0.43 (140) 4.5±0.4 (217) 2.1×10-10 Hematocrit 0.38±0.04 (142) 0.4±0.03 (217) 4.0×10-7 Sodium (Na) (mmol/l) 136±5.5 (49) 140±1.4 (49) 0.000016 Potassium (K) (mmol/l) 4.4±0.4 (49) 4.1±0.3 (49) 0.000038 Hemoglobin (g/l) 132±15 (142) 138±12 (217) 0.000100 C-reactive protein (CRP) (mg/l) 28±32 (64) 10±18 (136) 0.000130 Creatinine (µmol/l) 70±13 (13) 82±14 (50) 0.007600 Mean cell volume (MCV) (fl) 92±3.9 (142) 91±5.0 (217) 0.028500 Alanine aminotransferase (ALAT) (U/L) 21±18 (65) 41±90 (86) 0.044850 Alkaline phosphatase (AFOS) (U/L) 150±53 (16) 125±41 (25) 0.134720 Leukocytes (E9/l) 6.2±2.5 (140) 6.5±2.5 (217) 0.197680 Aspartate aminotransferase (ASAT) (U/L) 26±14 (38) 31±22 (29) 0.330570 Amylase (U/L) 205±45 (42) 192±75 (29) 0.399700

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

, F. Atroshi2

3 Department of Child Neurology, University of Helsinki, Finland

, M. Kaski1

[1] Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol

2 Department of Clinical Sciences, Pharmacology & Toxicology, University of Helsinki,

and M. Iivanainen1,3

M=mean value SD=standard deviation n=number of observations

SD=standard deviation n=number of observations

**Author details**

, T. Westermarck1

Oncol. 2000 ;22(1):62-5.

1 Rinnekoti Research Centre, FIN Espoo, Finland

P. Kaipainen1

Finland

**References**

M=mean value
