Theoretical insights into the degradation mechanisms, kinetics and eco-toxicity of oxcarbazepine initiated by OH radicals in aqueous environments.

As an anticonvulsant, oxcarbazepine (OXC) has attracted considerable attention for its potential threat to aquatic organisms. Density functional theory has been used to study the mechanisms and kinetics of OXC degradation initiated by OH radicals in aqueous environment. A total of fourteen OH-addition pathways were investigated, and the addition to the C8 position of the right benzene ring was the most vulnerable pathway, resulting in the intermediate IM8. The H-abstraction reactions initiated by OH radicals were also explored, where the extraction site of the methylene group (C14) on the seven-member carbon heterocyclic ring was found to be the optimal path. The calculations show that the total rate constant of OXC with OH radicals is 9.47 × 109 (mol/L)-1sec-1, and the half-life time is 7.32 s at 298 K with the [·OH] of 10-11 mol/L. Moreover, the branch ratio values revealed that OH-addition (89.58%) shows more advantageous than H-abstraction (10.42%). To further understand the potential eco-toxicity of OXC and its transformation products to aquatic organisms, acute toxicity and chronic toxicity were evaluated using ECOSAR software. The toxicity assessment revealed that most degradation products such as OXC-2OH, OXC-4OH, OXC-1O-1OOH, and OXC-1OH' are innoxious to fish and daphnia. Conversely, green algae are more sensitive to these compounds. This study can provide an extensive investigation into the degradation of OXC by OH radicals and enrich the understanding of the aquatic oxidation processes of pharmaceuticals and personal care products (PPCPs).

Chronic oxcarbazepine intoxication in a patient with primary antiphospholipid syndrome on maintenance haemodialysis.

WHAT IS KNOWN AND OBJECTIVE: Oxcarbazepine (OXC) is an antiepileptic drug. Patients suffering from chronic kidney disease with an estimated glomerular filtration rate below 30 ml/min/1.73 m2 require dose adjustments for OXC. CASE SUMMARY: A 31-year-old man was admitted with a history of diplopia, ataxia and dizziness attacks that had disappeared after a regular haemodialysis sessions for three months. Medical history was remarkable for primary antiphospholipid syndrome (APS). However, no signs of new-onset APS-related neurological involvement were present. Then, it was revealed that the patient had been using 2400 mg/day of OXC for four months, despite the prescription of half of this dose. Serum OXC level was 50 mcg/ml (reference: 3-35 mcg/ml) before a regular haemodialysis session. All symptoms disappeared in a few days after reducing to 1200 mg/day and never recurred. WHAT IS NEW AND CONCLUSION: We reported a chronic OXC intoxication in a patient on maintenance haemodialysis. To the best of our knowledge, it is the first chronic OXC intoxication case in the literature. It could be related to episodic removal of OXC and its metabolites via haemodialysis. Consequently, dose modification of drugs is a pivotal point in haemodialysis patients. Chronic drug intoxications must be kept in mind in haemodialysis patients with unexplained symptoms.

Oxcarbazepine induces mitotic catastrophe and apoptosis in NRK-52E proximal tubular cells.

Certain medicines including anticancer drugs, NSAIDs and antiepileptic drugs are known to cause drug-induced nephropathy. For example, antiepileptic drugs such as carbamazepine (CBZ) and valproic acid have been reported to cause damage to the proximal tubular cells. Although there has been a great deal of research concerning the nephrotoxicity of CBZ, little is known about that of oxcarbazepine (OXC), a derivative of CBZ. To investigate the molecular mechanism underlying renal proximal tubular cell death caused by OXC, we examined alterations in the gene expression profile of NRK-52E proximal tubular cells during OXC exposure. DNA microarray analysis revealed that the levels of genes related to mitotic processes including chromosomal and cytoplasmic segregation, progression to G2/M phase, and formation of the mitotic spindle are increased after exposure to 50 µM OXC for 6 h. Cell cycle analysis by flow cytometry showed that OXC at concentrations between 25 and 100 µM induces G2/M arrest. We also found that OXC significantly increases histone H3 phosphorylation, indicative of mitotic cells. These results imply that OXC induces cell cycle arrest at the mitotic phase. Immunofluorescence analysis showed monopolar spindles, which are formed in response to centrosome separation defects, in OXC-treated cells. We also show that OXC suppresses the phosphorylation of PLK1, which is involved not only in the activation of the kinesin family of motor proteins for centrosome separation and bipolar spindle assembly, but also in the cleavage of centrosomal proteins. Thus, our results indicate that OXC inhibits centrosome separation by reducing the activation of PLK1, which leads to the formation of an abnormal spindle and induces mitotic catastrophe and apoptosis in NRK-52E cells.

The neurotoxic effects of prenatal gabapentin and oxcarbazepine exposure on newborn rats.

AIM: Teratogenicity is a problematic issue for pregnant women because of X-ray radiation, drugs, and genetic and unknown variables. First-generation antiepileptic drugs (AED) like valproic acid are well-known teratogens for developing fetuses. However, their usage is necessary in order to prevent maternal seizures. The underlying mechanism of birth defects associated with AED exposure remains unclear and information about the neurotoxic effects of prenatal exposure to AED is still limited. Oxcarbazepine (OXC) and gabapentin (GBP) are second-generation AED. It still remains unclear how much these drugs are safe during pregnancy. This study aimed to investigate whether any neurotoxic effect of OXC and GBP in utero exposure on the developing brain. METHODS: Eighteen pregnant Wistar albino rats were divided into six groups. The first group was exposed to OXC at 100 mg/kg/day, the second to GBP at 50 mg/kg/day, and third to saline (0.9% NaCl) at 1.5 ml/day between the first and the fifth days of gestation. The same procedure was applied at the same dosages between the 6th and the 15th days of gestation for the 2nd three groups. Five female offspring (total n = 30, 45 days old) were taken from each group and stereological methods were applied in order to analyze the total and dopaminergic neuron number of the substantia nigra pars compacta (SNc). CONCLUSION: The result is that the OXC and GBP exposure at different gestational periods may not give rise to congenital malformation and it appears that the GBP exposure during the organogenesis period proliferatively affects the total number of neurons.