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Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The therapeutic range of topiramate (TPM) blood level is not set because the efficacy and safety are not considered to be related to the level. However, the therapeutic target without side effects is necessary, so the optimal range of TPM blood level was analyzed in this study., Study Question: This study was conducted to evaluate the efficacy of TPM over 2 years and the utility of measuring blood levels of TPM during the follow-up of epileptic patients., Study Design: Thirty patients (18 males, 12 females; age range, 6 months-15 years) were treated with TPM for epilepsy. The initial dosage of TPM was 1-3 mg·kg·d. If the effect proved insufficient after 2 weeks, the dosage was increased to 4-9 mg·kg·d., Measures and Outcomes: Blood levels of TPM were measured by liquid chromatography-tandem mass spectrometry at 1, 6, 12, and 24 months after levels reached steady state. The efficacy of TPM was evaluated by the reduction in epileptic seizure rate (RR) at the time of blood sampling. Statistical analysis was performed using the Mann-Whitney U test., Results: A positive correlation was seen between blood levels and maintenance dosages, but no correlation was observed between blood levels and RR. Any significant difference was not identified in TPM levels between the effective group (RR ≥50%) and the ineffective group (RR <50%; P = 0.159). In the subgroup of patients who did not use valproic acid, a significant difference in TPM levels was apparent between the effective and ineffective groups (P = 0.029). The optimal range of TPM was advocated 3.5-5.0 μg/mL. The optimal range was set, so that ranges did not overlap between the effective and ineffective groups. No patients experienced any side effects., Conclusions: Measuring blood levels of TPM based on the classification of concomitant drugs and adjusting the dosage to reach the optimal range were recommended.

Topiramate (TPM) is a second-generation antiepileptic drug (AED), acting on drug-resistant epilepsy. The aim of the study was to evaluate the influence of the dose, use of other AEDs on TPM plasma concentration (C p ), and frequency of epileptic seizures. A cross-sectional analytical study was developed with patients aged 18-60 years, for diagnosis of drug-resistant epilepsy, using TPM in monotherapy or associated with other AEDs. The following variables were analyzed: age, frequency of epileptic seizures, pharmacotherapeutic regimen with its respective doses, adherence to medication treatment, and adverse events score. Thirty-seven patients were included, 83.8% of the patients presented C p below the therapeutic range. Multiple linear regression estimated that the increase of 1.0 mg/kg/d promoted an increase of 0.68 μg/mL in TPMC p , while the use of inducers predicted a reduction of 2.97 μg/mL (P < .001). Multiple Poisson regression predicts that an increase of 1.0 μg/mL in TPMC p decreased the patient's chance of presenting seizures, and patients using AED inducers were about ten times more likely to present seizures than those who do not use (P < .001). In addition, for patients using AED inducers with C p below the therapeutic range, the mean number of seizures per month was greater than those with C p within the therapeutic range. The prescribed dose and the use of AED inducers influence C p of TPM, likewise the low C p of first-line AEDs and of the adjuvant in the treatment, TPM, as well as low TPM dose seem to affect the control of epileptic seizures., (© 2018 John Wiley & Sons Australia, Ltd.)