Effects of Low- and High-Dose Valproic Acid and Lamotrigine on the Heart in Female Rats.

Epilepsy is a chronic neurological disease that affects more than 50 million people worldwide. Antiepileptic drugs (AEDs) are the mainstay of treatment for most patients with epilepsy. However, AEDs have been reported to be associated with adverse cardiac effects. In this study, it was aimed to investigate the possible cardiac effects of low-dose (LD) and high-dose (HD) treatment of valproic acid (VPA) and lamotrigine (LTG), which are commonly used AEDs, in rats without epilepsy. Rats were randomly grouped as control, LD-VPA, HD-VPA, LD-LTG, and HD-LTG. The cardiac effects of AEDs were evaluated using immunohistological, biochemical, and hemodynamic parameters. A dose-dependent increase in the intensity of caspase-3 staining was detected in the VPA and LTG groups. The intensity of connexin-43 and troponin-T staining in the VPA groups and desmin staining in the LTG groups was significantly reduced. Biochemically, HD-VPA and HD-LTG administrations caused a significant increase in MDA level in myocardial tissue. In addition, as a result of hemodynamic evaluations, cardiac functions were found to be affected and blood pressure increased in HD-LTG group. The results of present study support that VPA and LTG treatment can increase cardiac risk markers.

Protective Effect of Flax Seed on Brain Teratogenicity Induced by Lamotrigine in Rat Fetuses.

The objective of this study was to assess the effects of the hydroalcoholic extract of flax seed on the teratogenic activity of lamotrigine in the brain of fetuses of rats who had received the drug. In this experimental study, 40 female rats were assigned randomly into four groups and after mating and confirming the vaginal plug, the control animals (group 1) were kept with no intervention, and the other three experimental groups were intraperitoneally injected with respective lamotrigine (75 mg/kg), and 100 and 200 mg/kg of flax seed hydroalcoholic extract. The drug was administered during the organogenesis period. Rats were sacrificed at the 20th day of gestation (one day before term) and fetuses were macroscopically examined, weighed and crown-rump length measured. Fetal brain specimens were processed for H&E and for histological study, using the ImageJ software. Results showed that fetuses of the experimental groups that received lamotrigine had reduced body weight, prefrontal cortical and hippocampal thickness, and pyramidal neurons in the hip-pocampus; Nevertheless, these factors were improved by high-dose administration of flax seed in the experimental group 3 and 4. Our research concludes that lamotrigine negatively influences the development of brain in rats and flax seed has a protective impact on these complications.

Lamotrigine Toxicosis Treated with Intravenous Lipid Emulsion Therapy in a Dog.

A female spayed dachshund/mixed-breed dog was evaluated following ingestion of lamotrigine tablets with subsequent rapid onset of vomiting, diarrhea, and generalized tremoring. On initial examination, the dog was moderately obtunded and nonambulatory with intermittent myoclonus and hyperesthesia. Electrocardiogram revealed sinus tachycardia with prolongation of the QT interval. Intravenous lipid emulsion (ILE) infusion was initiated, with reduction in tremoring and improved patient mentation being noted after ∼20 min of therapy. An elevated cardiac troponin I value measured at 1.02 ng/mL the day after presentation. Serum toxicological assay revealed marked reduction in serum lamotrigine levels following ILE and continued reduction during hospitalization. The dog's clinical signs resolved, corrected QT interval returned to normal, and the patient was discharged 38 hr after presentation. Individual cases of lamotrigine toxicosis have not been fully reported in veterinary literature. This case report documents the rapid onset of clinical signs including neurologic dysfunction, cardiac arrhythmias, and transient corrected QT prolongation. Serial serum concentrations of lamotrigine showed a rapid reduction with ILE therapy and corresponded with clinical recovery, suggesting efficacy of ILE treatment in this case.

Safety evidence on the administration of Fucus vesiculosus L. (bladderwrack) extract and lamotrigine: data from pharmacokinetic studies in the rat.

Fucus vesiculosus is often incorporated in weight loss dietary supplements to improve weight loss in overweight adults. Obesity is a common condition in epilepsy patients and is indeed increasing in refractory epilepsy and in patients under polytherapy. Since lamotrigine (LTG) is a first-line antiepileptic drug, used in monotherapy or adjunctive therapy, the main objective of this work was to investigate the potential pharmacokinetic-based interactions between F. vesiculosus and LTG in rats. In a first pharmacokinetic study, a single oral dose of F. vesiculosus extract (575 mg/kg, p.o.) was co-administered with a single-dose of LTG (10 mg/kg, p.o.). In a second study, rats were orally pretreated with F. vesiculosus extract (575 mg/kg/day, p.o.) for 14 days and received LTG (10 mg/kg, p.o.) on the 15th day. In the control groups, rats received water instead of the extract. After LTG administration, blood samples were taken until 96 h post-dose, and LTG concentrations measured in plasma were submitted to a non-compartmental pharmacokinetic analysis. The co-administration of F. vesiculosus extract and LTG caused no significant changes in the drug kinetics. However, the repeated pretreatment with F. vesiculosus extract significantly reduced the peak concentrations of LTG and caused a slightly decrease in the extent of systemic drug exposure. Overall, based on these results, no significant clinical impact is expected from the administration of F. vesiculosus dietary supplements and LTG.