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Carbamazepine (CBZ) is a medication used commonly in epilepsy. Decreases in free T4 levels simulating central hypothyroidism have been reported, although the clinical significance is still unclear. We present a 24-year-old man with Bardet-Biedl syndrome (BBS) who was found to have isolated biochemical central hypothyroidism. BBS is a ciliopathy occasionally associated with anterior pituitary dysfunction. While taking CBZ for epilepsy, his TSH was 1.73 mIU/L (reference range: 0.20–4.00 mIU/L) with a low free T4 of 6.6 pmol/L (reference range: 10.0–26.0 pmol/L). Pituitary MRI was normal. Although treated with levothyroxine initially, his apparent biochemical central hypothyroidism was later recognised as secondary to CBZ drug effect. This was confirmed with a normal free T4 of 12.2 pmol/L while he was off CBZ and levothyroxine. Despite the association between CBZ and biochemical central hypothyroidism, nearly all patients remain clinically euthyroid. This effect is reversible and recognition could lead to reductions in unnecessary thyroid replacement therapy if CBZ is discontinued.

A 48-year-old man who is a known case of bipolar disorder was maintaining well on a combination of carbamazepine and quetiapine for 3 years until he developed fever, severe leucopenia and lymphadenopathy, along with significant loss of weight and appetite. A thorough investigation revealed Kikuchi’s disease as a likely histological diagnosis. Carbamazepine was discontinued and quetiapine was titrated for the management of psychiatric symptoms. The patient gradually made good recovery following discontinuation of carbamazepine and the diagnosis of drug-induced myelosuppression was retained. Clinicians need to be aware of the adverse effects of medications being used for long-term prophylaxis and other possible conditions that may change the course of drug effects.

Background/purpose Taiwan Drug-Injury Relief System (TDRS) has been implemented since 1999. More than 60% of the approved applications were associated with severe cutaneous adverse reactions (SCARs). Studies assessing SCARs using real-world evidence are very limited. TDRS offers abundant case information as a source of real-world evidence to investigate the characteristics of SCARs in Taiwan. The purpose of this study is to understand the trends and characteristics of SCARs in Taiwan. Methods Applications from Drug-Injury Relief Database (TDRD) from 1999 to 2016 were retrospectively analyzed. Results A declining trend in SCARs application was noticed after 2012, and 952 applications of SCARs were identified. The most common subtypes of SCARs were SJS/TEN (n = 455/206), DRESS (n = 228), GBFDE (n = 34) and AGEP (n = 18). The most common culprit drugs were allopurinol, carbamazepine, phenytoin, diclofenac and lamotrigine for SJS/TEN; allopurinol, phenytoin, co-trimoxazole, carbamazepine and phenobarbital for DRESS; mefenamic acid for GBFDE; non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibacterials for AGEP. The proportions of mortality cases were 28.9% for SJS/TEN; 36% for DRESS; 11.8% for GBFDE and 5.6% for AGEP. The mean latent period of SJS/TEN, DRESS, GBFDE and AGEP were 21.8 days, 29.2 days, 3.3 days and 6.7 days, respectively. Conclusions The approved drug-injury relief applications associated with SCARs were mainly SJS, TEN and DRESS. The most common culprit drugs were antiepileptics, antibacterials, antigout agents, and NSAIDs. The latent periods showed some distinct features for different types of SCARs. In light of the high mortality rate, public awareness and vigilance of SCARs are crucial for the patient safety.

Introduction The type of blood collection tube used when obtaining samples for therapeutic drug monitoring (TDM) has important implications on the accuracy of results. Serum tubes without a gel separator are currently considered best practice. We sought to evaluate the performance of of Barricor™, a novel plasma tube that utilizes an inert mechanical separator, as well as a gel-based tube (PST™) for testing acetaminophen, digoxin, gentamicin, methotrexate, phenobarbital, phenytoin, salicylate, vancomycin, valproic acid, carbamazepine, and theophylline on a Roche Cobas® 8000 platform. Methods Paired patient samples were collected from individuals taking at least one of the medications evaluated. These were supplemented with spiked specimens to ensure a minimum of 40 paired samples per drug. All drugs were measured within two hours of collection on Roche e602 or c502 instruments. Deming regression was used to assess bias between Barricor™ vs serum and PST™ vs serum. Seven-day refrigerated stability was also assessed in Barricor™, PST™, and serum tubes in a subset of samples (n=10) for each drug. Results Drug concentrations in Barricor™ were similar to serum for each drug assessed. In contrast, a negative bias was observed in PST™ compared to serum tubes for carbamazepine (-7.6%) and phenytoin (-6.8%) although this did not surpass our total allowable error goal of 10%. All drugs recovered within ±10% of baseline value when samples were stored refrigerated for 7 days except for carbamazepine, phenytoin, and phenobarbital where significant analyte loss was observed within the first day in PST™ tubes. Conclusion Barricor™ tubes are a suitable alternative to serum for TDM on the Roche Cobas® 8000 platform.

Introduction Mutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders. Case report The patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as “variants of uncertain significance” and later upgraded to “likely pathogenic” based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNAGln aminoacylation with the c.1574G > A variant. Conclusion We describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.

We aim to report the major congenital malformation (MCM) rates for new and old anti-epileptic drugs (AED) exposures during the first trimester of pregnancy in women with epilepsy (WWE).We extracted relevant data on drug exposure and malformation rate from the records of a prospective observational registry (Kerala Registry of Epilepsy and Pregnancy) for all completed pregnancies between 1998 and 2019. A comprehensive and uniform criterion with detailed guideline was used for assessment of malformations. We employed generalised linear model to generate adjusted incidence rate ratios (aIRR) of MCM in AED exposed group as compared to AED unexposed group, after adjustment for age and educational status of mothers' and epilepsy classification.The unadjusted MCM rate was 6.2% for all the infants included in the study (148/2328); 4.7% for the unexposed group (16/340), and 6.6% for the exposed group (132/1988). The aIRR of MCM as compared to unexposed group was similar for all monotherapies; lamotrigine (0.50; 95% CI 0.07-3.68), levetiracetam (1.16; 0.43-3.11), oxcarbazepine (1.61; 0.62-4.21) valproate (1.71, 0.93-3.19), phenytoin (1.21, 0.51-2.90), carbamazepine (0.99, 0.54-1.82), and phenobarbitone (1.20, 0.52-2.74). However, the point estimates suggest least risk with lamotrigine and highest risk with valproate. Polytherapy with high-dose valproate carried significantly higher risk of MCM as compared to the unexposed group (aIRR=4.12; 2.18-7.79, p0.001). The aIRR of GTCS during pregnancy was 1.63 (95% CI 1.12-2.37, p = 0.011) for monotherapy with new AEDs (lamotrigine, levetiracetam or oxcarbazepine) as compared to old AEDs (phenobarbitone, phenytoin, carbamazepine, or valproate).The MCM risk was significantly higher for polytherapy with high dose valproate. It did not differ substantially between different AED monotherapies although point estimate was lowest with lamotrigine. Pregnant women on new AEDs report higher likelihood of GTCS than women on old AEDs during pregnancy.

BACKGROUND Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS Dexamethasone significantly inhibited T3 uptake at 10 μM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 μM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 μM and 68% at 100 μM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 μM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Thyroid hormones play an essential role in central nervous system development, normal physiological brain function, and repair mechanisms. On one hand, thyroid hormone alterations influence cortical excitability, and on the other hand antiseizure medications (ASMs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective. We performed a systematic review of the current literature on epilepsy, ASMs, and thyroid hormone metabolism according to PRISMA guidelines. Forty-seven studies were included. Most studies were retrospective cross-sectional studies (n = 25) and investigated thyroid function alterations in patients on older ASMs such as phenobarbital, phenytoin, carbamazepine, and valproate. Overall, almost one third of patients with epilepsy had thyroid hormone alterations, especially patients on valproate (25%) and carbamazepine (10%-25%). Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age (p = .004), female sex (p = .014), longer duration of epilepsy (p = .001), intractable epilepsy (p = .009), and polytherapy. Studies on newer ASMs are also limited, and further studies on an interplay with thyroid hormone homeostasis are essential to improve the care for epilepsy patients. ASMs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on ASMs, especially those with refractory epilepsy and those on polytherapy. We provide a practical guidance for thyroid function monitoring for the clinician taking care of patients on ASMs.

What is known and objective Long-acting injectable (LAI) antipsychotics are an integral part of mental health treatment. Modifying an LAI regimen poses several challenges because of the extended half-life of the drug. Case summary An acutely psychotic patient with schizoaffective disorder received aripiprazole lauroxil without resolution of symptoms. She was started on a previously successful regimen of oral fluphenazine. Due to continued psychosis, oral carbamazepine was initiated to expedite the LAI's metabolism allowing subsequent doses of fluphenazine to impart activity. What is new and conclusion Potent cytochrome enzyme inducers may help in transitioning patients from LAI antipsychotics to other therapies.

Background Anti-epileptic drugs have different effects on neonatal seizures, and new agents have been widely used in recent years. Meanwhile, significant differences still exist in the treatment for neonatal seizures, whether in choice of drug or in duration of treatment. And with the increase in options for treatment, the best choice of second-line treatment has not been recommended. Methods The MEDLINE, the Cochrane Library, Web of Science, Embase and clinicaltrials.gov databases were searched (January 1, 1960 to October 20, 2020). Randomized controlled trials (RCTs) or observational investigations studying anti-epileptic drugs for neonatal seizures were selected. And then we conducted a network meta-analysis and examined comparative efficacy of the first-line and second-line anti-epileptic drugs for neonatal seizures. Results Data were extracted from 11 included studies by 2 independent investigators. Random effects models were used to estimate odds ratios (ORs). We performed direct meta-analyses with a random effects model and network meta-analyses for first-line and second-line drugs. Five published RCTs and 6 observational investigations with 1333 patients and 6 interventions contributed to the analysis. Conclusion We recommend phenobarbital as the first-line drug for neonatal seizures. In addition, there is a tendency for levetiracetam to be an effective second-line treatment for neonatal seizures after failure of first-line drugs.

Background Epilepsy can be treated with antiepileptic drugs (AEDs) which may have psychiatric and behavioral side effects. Additionally, the availability of new AEDs has increased, and our understanding of variability to combinations of several AEDs has evolved. Based on the treatment outcomes of carbamazepine, valproate, and clonazepam, this study aims to compare the cognitive function, personality, and psychological issues associated with these drugs and evaluate seizure-related factors related to them. Only 139 participants were included. Clonazepam was used as an add-on antiepileptic drug. Participants were categorized into five groups: group 1, carbamazepine; group 2, valproate; group 3, carbamazepine and clonazepam; group 4, valproate and clonazepam; and group 5, epileptic patients without AED. All participants were assessed using the Wechsler Adult Intelligence Scale (WAIS), Structured Interview for the Five-Factor Personality Model (SIFFM), Hamilton Anxiety and Depression Rating Scale, and Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Results In the WAIS, group 1 had the worst mean of verbal intelligence quotient (IQ). Moreover, group 3 was more vulnerable in symptomatic response in all subscales of MMPI-2 except the masculinity–femininity subscale and a high percentage in moderate severity of anxiety and depression in the Hamilton scales. Conclusions The use of clonazepam and carbamazepine might increase the incidence of behavioral problems especially increased severity of anxiety and depression and decreased performance IQ compared with either clonazepam or carbamazepine alone. Moreover, patients with carbamazepine treatment might have more personality changes and lowered verbal IQ than others.

It is challenging to balance the fetal risks associated with the use of antiepileptic drugs (AEDs) against maternal and fetal risks of seizure worsening, and therefore it is very important to define and distinguish the possible risks entailed by different AEDs. This paper aims to undertake a comprehensive review regarding the possible risks of four classical (phenytoin, carbamazepine, phenobarbital, and valproate) and two newer (lamotrigine and levetiracetam) AEDs during pregnancy. The review focuses on major and organ-specific malformations, dose-dependent risks, mono vs polytherapy, and clinical pharmacokinetics. A discussion regarding the safety of AED use during breastfeeding is also provided.

Background Trigeminal neuralgia (TN) is a severe form of pain that affects the daily activities of a patient. Transcutaneous electrical nerve stimulation (TENS) therapy is an emerging option for the treatment of acute and chronic pain. The aim of this study was to evaluate the effect of TENS therapy as an adjunct to drug therapy for the treatment of TN. Methods A total of 52 patients diagnosed with TN according to the International Classification of Headache Disorders (version 3) were included. Each patient was randomized to either the TENS or placebo TENS groups. Intervention was given in continuous mode and 100-Hz frequency for 20 mins biweekly for 6 weeks. Parameters were measured at baseline, TENS completion and 3 months, 6 months, and 1 year of follow up. The parameters observed were mean carbamazepine dose, mean visual analog scale (VAS) score, mean present pain intensity (PPI) score, and functional outcome. Non-parametric analyses, one-way ANOVA and the Kruskal-Wallis test were applied for intragroup comparisons, while the Mann-Whitney U test and independent t-test were used for intergroup comparisons of variables. The chi-square test was applied to analyze categorical data. Results Compared to the placebo TENS group, the mean dose of carbamazepine in the TENS group was significantly reduced at TENS completion, as well as at 6 months and 1 year follow up. Changes in mean VAS score, mean PPI score, and functional outcome did not show significant differences between the groups (P>0.05). Conclusion TENS therapy does not lead to any changes in pain levels but it may reduce the mean dose of carbamazepine when used as an adjunct treatment in patients with TN.

Investigation of associated risk factors of valproic acid (VPA)–induced tremor helped in increasing tolerance and optimizing treatment scheme individually. To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24 months; OR = 3.294, p = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047). Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor.

Today, millions of people suffer from epilepsy, one of the most common chronic neurological diseases worldwide. Carbamazepine is a first-line drug used in the treatment of epilepsy. High performance liquid chromatographic and spectrophotometric methods have been developed for the determination of carbamazepine in tablet dosage forms. UV spectrums were recorded in the wavelength range of 200-800 nm using methanol solvent, and the wavelength for determining carbamazepine was selected as 286 nm. LC analysis was performed using Agilent Extend-C18 column and mobile phase composed of KH2PO4 solution(pH: 3.5) and acetonitrile (40:60 v/v) at a flow rate of 1.2 mlmin-1. These analytical methods were validated in agreement with the International Conference on Harmonization (ICH) guidelines using the following analytical parameters: specificity, linearity, precision, accuracy, detection and quantification limits, and robustnes. Analytical methods showed wonderful linearity (r2>0.999) in the concentration range of 5-25 μg mL-1 for boths methods. Precision (R.S.D%

The purpose of the present study was to investigate the effect of crystal facets on solution-mediated phase transformation (SMPT) at cocrystal surfaces during dissolution in aqueous media. Previous...

A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.

Diverse ethnic genetic populations display variability in the risk regarding anti-seizure medicine (ASM)-induced severe cutaneous adverse reactions (SCARs). However, clinical and epidemiological data on ASM-induced SCARs in Asians is limited.We conducted a retrospective, post-market study until April 30, 2020 using VigiBase® for demographic characteristics, causative ASMs, complications and mortality. The study included adverse events as classified by Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries of SCARs, mainly Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and SJS/TEN overlap reported for ASMs.A total of 694,811 adverse events were reported across the world while using ASMs. Of this, skin and subcutaneous tissue adverse events were 122,885 (17.6%). Among ASM-induced skin and subcutaneous tissue adverse events, SJS, TEN, DRESS and SJS/TEN overlap represented 11,181 (9.1%), 3,645 (3.0%), 5,106 (4.1%) and 6 (0.004%) cases, respectively. Female SJS/TEN/DRESS patients were 54.1%, and 75% of them were adults (18Y). Nearly 64% of the ASM-induced SCARs were serious and culminated in death (3.5%), life-threatening conditions (11.5%), and hospitalization/prolonged hospitalization (43.5%) of patients on ASM therapy. Carbamazepine (31.6%), phenytoin (29.6%), lamotrigine (24.3%), valproic acid (6.4%) and phenobarbital (5.7%) are the most commonly used ASMs linked with SCARs. ASMs associated with significantly higher risk of SCARs in Asians were carbamazepine [n = 3265, ROR 3.55 (95% CI 3.38-3.72, P 0.0001)], lamotrigine [n = 1253, ROR 3.90 (95% CI 3.63-4.18, P 0.0001)], gabapentin [n = 85, ROR 3.58 (95% CI 2.79-4.60, P 0.0001)], pregabalin [n = 68, ROR 3.16 (95% CI 2.40-4.16, P 0.0001)], clonazepam [n = 53, ROR 3.19 (95% CI 2.31-4.41, P 0.0001)], lorazepam [n = 31, ROR 3.07 (95% CI 2.06-4.59, P 0.0001)] and acetazolamide [n = 28, ROR 3.90 (95% CI 2.45-6.21, P 0.0001)].Based on our study, carbamazepine, lamotrigine, gabapentin, pregabalin, clonazepam, lorazepam, and acetazolamide are the most common causative ASMs for SCARs in the Asian population.

Ding Tang,1 Xufen Zhang,1 Yani Xu,1 Linglin Dai,1 Jianlan Sun,1 Hantong Hu,2 Huangwei Jiang,3 Ping Jin,3 Lifang Chen,2 Jianqiao Fang4 1The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Acupuncture, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Radiological, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The Third Clinical Medical College of Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Lifang ChenDepartment of Acupuncture, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, XiHu District, Hangzhou, Zhejiang, 310005, People’s Republic of ChinaEmail clfang@163.comJianqiao FangZhejiang Chinese Medical University, NO. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaEmail fangjianqiao7532@163.comObjective: To verify the efficacy of electroacupuncture (EA) on classical trigeminal neuralgia (CTN), and to observe the brain functional status of patients with CTN and the intervention effects of EA on brain function by resting-state functional magnetic resonance imaging (rs-fMRI).Methods and Analysis: Thirty CTN patients will be randomly divided into EA combined with carbamazepine group and carbamazepine group in 2:1 ratio by using a random number table. Patients in EA combined with carbamazepine will receive EA treatment and carbamazepine for four weeks. The carbamazepine group will only receive carbamazepine treatment. VAS (visual analogue scale), HAMA (Hamilton Anxiety Scale), HAMD (Hamilton Depression Scale) and SF-36 (short form 36 health survey) will be performed before, after four-week treatments and at three-month follow-up in CTN patients. Six CTN patients will be randomly selected from EA combined with carbamazepine group and carbamazepine group, respectively, before treatment, and twelve paired healthy participants will be recruited at the same time. The twelve CTN patients will be scanned by rs-fMRI before and after treatment, and the healthy participants will be scanned by rs-fMRI only at baseline. Regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analysis will be carried out to compare the dysfunctional brain regions between CTN patients and healthy participants, as well as the differences between two groups of patients with CTN after treatment.Trial Registration: ChiCTR-1900027873.Keywords: electroacupuncture, trigeminal neuralgia, pre-experimental, fMRI, randomized controlled trial, protocol

Aim: We evaluated the potential influence of genetic ( CYP3A5, EPHX1, NR1I2, HNF4A, ABCC2, RALBP1, SCN1A, SCN2A and GABRA1) and nongenetic factors on carbamazepine (CBZ) response, adverse drug reactions and CBZ plasma concentrations in 126 Mexican Mestizos (MM) with epilepsy. Subjects & methods: Patients were genotyped for 27 variants using TaqMan® assays. Results: CBZ response was associated with NR1I2 variants and lamotrigine cotreatment. CBZ-induced adverse drug reactions were related to antiepileptic polytherapy and SCN1A rs2298771/rs3812718 haplotype. CBZ plasma concentrations were influenced by NR1I2-rs2276707 and -rs3814058, and by phenytoin cotreatment. CBZ daily dose was also influenced by NR1I2-rs3814055 and EPHX1-rs1051740. Conclusion: Interindividual variability in CBZ treatment was partly explained by NR1I2, EPHX1 and SCN1A variants, as well as antiepileptic cotreatment in MM with epilepsy.

We planned this experimental study to investigate the effect of carbamazepine (CMZ) on the endometriotic implants. Rats were randomised into four groups after endometriosis surgery. Drinking water was given to the sham group, 0.2 mg/kg oestradiol valerate (EV) to the EV group, 100 mg/kg/day CMZ to the CMZ group, and 0.2 mg/kg EV and 100 mg/kg/day CMZ to the EV-CMZ group. The endometrium of the rats using CMZ stained more intensely with cytochrome P450-3A4 (CYP3A4) enzyme. No endometrial hyperplasia was found in these rats. Endometriotic implants weight was found to be higher in these rats. There was no difference between the groups in terms of staining of the endometriotic implants with CYP3A4 enzyme. Endometriotic implants were less stained with the CYP3A4 enzyme than the endometrium. According to our results, CMZ does not increase the destruction of oestrogen in the endometriotic implants, unlike the endometrium. It may even cause the lesion to enlarge.Impact statementWhat is already known on this subject? Endometriosis is an oestrogen-dependent, progressive disease. Carbamazepine (CMZ) is known to increase oestrogen degradation by activating the cytochrome P450-3A4 (CYP3A4) enzyme. CMZ can be used in the treatment of endometriosis because it increases oestrogen breakdown in tissues.What do the results of this study add? CMZ can protect the endometrium against hyperplasia by increasing the amount of CYP3A4 enzyme in the endometrium. This effect could not be demonstrated in the endometriotic implants. The presence of CYP3A4 enzyme less in the endometriotic implants than in the endometrium may explain this situation. In addition, the fact that CMZ does not increase the enzyme in the endometriotic implants may contribute to this situation.What are the implications of these findings for clinical practice and/or further research? CMZ may not be a suitable alternative in the treatment of endometriosis. However, it may protect against endometrial hyperplasia. Clinical studies are needed for this effect.

Objective Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role. Methods We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Botzinger complex (PreBotC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs. Results We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBotC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBotC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBotC neurons. Significance Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Botzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies.

Entrectinib is a selective inhibitor of ROS1/TRK/ALK kinases, recently approved for oncology indications. Entrectinib is predominantly cleared by cytochrome P450 (CYP) 3A4, and modulation of CYP3A enzyme activity profoundly alters the pharmacokinetics of both entrectinib and its active metabolite M5. We describe development of a combined physiologically based pharmacokinetic (PBPK) model for entrectinib and M5 to support dosing recommendations when entrectinib is co-administered with CYP3A4 inhibitors or inducers. A PBPK model was established in Simcyp® Simulator. The initial model based on in vitro–in vivo extrapolation was refined using sensitivity analysis and non-linear mixed effects modeling to optimize parameter estimates and to improve model fit to data from a clinical drug–drug interaction study with the strong CYP3A4 inhibitor, itraconazole. The model was subsequently qualified against clinical data, and the final qualified model used to simulate the effects of moderate to strong CYP3A4 inhibitors and inducers on entrectinib and M5 pharmacokinetics. The final model showed good predictive performance for entrectinib and M5, meeting commonly used predictive performance acceptance criteria in each case. The model predicted that co-administration of various moderate CYP3A4 inhibitors (verapamil, erythromycin, clarithromycin, fluconazole, and diltiazem) would result in an average increase in entrectinib exposure between 2.2- and 3.1-fold, with corresponding average increases for M5 of approximately 2-fold. Co-administration of moderate CYP3A4 inducers (efavirenz, carbamazepine, phenytoin) was predicted to result in an average decrease in entrectinib exposure between 45 and 79%, with corresponding average decreases for M5 of approximately 50%. The model simulations were used to derive dosing recommendations for co-administering entrectinib with CYP3A4 inhibitors or inducers. PBPK modeling has been used in lieu of clinical studies to enable regulatory decision-making.

International audience; Objective: Epilepsy is a major neurological disorder that requires long-term medical treatment. Once epilepsy is diagnosed, people with epilepsy face many difficulties in accessing treatment (treatment gap). Our objective was to assess the situation regarding the availability, price, affordability, and quality of anti-seizure medication (ASM), which are major determinants of access to treatment. Method: A cross-sectional study was performed in provincial/district hospitals and private pharmacies in urban and rural areas in Cambodia. Data on ASM availability and price were obtained through drug suppliers. Affordability was estimated as the number of day wages the lowest-paid government employee must work to purchase a monthly treatment. Samples of ASM were collected, and the quality of ASM was assessed through Medicine Quality Assessment Reporting Guidelines. Results: Out of 138 outlets visited, only 72 outlets (52.2% [95% CI 43.5-60.7]) had at least one ASM available. Phenobarbital 100 mg was the most available (35.5%), followed by carbamazepine 200 mg (21.7%), phenobarbital 50 mg (11.6%), sodium valproate 500 mg (9.4%), and phenytoin 100 mg (9.4%). In provincial/district hospitals, ASM was provided free of charge. In private pharmacies, affordability for phenobarbital 50 mg and 100 mg was the best, with 0.6 and 0.5 days, respectively, compared to phenytoin 100 mg (1.8 days), and other ASM. No counterfeit ASM was found in this study. Phenytoin sample presented the worst quality (33.0%) compared to carbamazepine (27.8%), and other ASM. Significance: A lack of access to affordable and effective ASM due to low availability and poor quality of ASM was identified. Our research highlights the need for future policy efforts to ensure the quality of ASM and improve their availability. This can be achieved by involving the calculation of their annual needs for these drugs and increasing the national production of ASM.

Antiepileptic mood stabilizers (AED-MS) are often used to treat bipolar disorder (BD). Similar to other mood disorder medications, AED-MS treatment response varies between patients. Identification of biomarkers associated with treatment response may ultimately help with the delivery of individualized treatment and lead to improved treatment efficacy. Here, we conducted a narrative review of the current knowledge of the pharmacogenomics of AED-MS (valproic acid, lamotrigine and carbamazepine) treatment response in BD, including genetic contributions to AED-MS pharmacokinetics. Genes involved in neurotransmitter systems and drug transport have been shown to be associated with AED-MS treatment response. As more studies are conducted, and experimental and analytical methods advance, knowledge of AED-MS pharmacogenomics is expected to grow and contribute to precision medicine in BD.

Carbamazepine has demonstrated anticonvulsant properties and is used for a variety of indications in psychiatry and neurology. Total daily doses typically range from 200 to 1200 mg/d, generally divided into 2 doses. Carbamazepine has a broad side-effect profile but is not typically thought to produce high fevers in the absence of a hypersensitivity syndrome. This is a case of a probable adverse drug reaction to carbamazepine consisting of fever without severe major organ involvement. In this instance, a patient in a manic episode with psychotic features was briefly transferred to a COVID-19 unit to rule out coronavirus infection before the fever resolved.

Background Carbamazepine (CBZ) is a wildly used anti-epileptic drug (AED). Increasing evidence suggested that polymorphisms in Epoxide Hydrolase1 (EPHX1) gene are associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of CBZ, albeit the results were inconsistent. Methods A literature search on PubMed, Embase, and Cochrane Library was conducted to identify eligible studies published between 1974 and 2020. A meta-analysis was performed and the standardized mean difference (SMD) and 95% confidence interval (95% CI) were estimated using a random-effects model. The heterogeneity and leave-one-study-out sensitivity analyses of each article and the publication bias were also performed. All the statistical analyses were performed using STATA 14.0. Results A total of 6 articles with 1746 subjects were included in this meta-analysis. A significant correlation was detected between EPHX1 rs1051740 T > C polymorphisms and decreased plasma concentration of CBZ (TT vs CC: SMD = 0.34, P C variation (P = 0.637), while subgroup analyses showed an association with plasma CBZ concentration in the non-Asian group (P G polymorphisms with plasma CBZ concentration was not detected (AA vs GG:SMD = 0.54, P = 0.102; AA vs AG:SMD = −0.05, P = 0.670; AG vs GG: SMD = 0.86, P = 0.107), subgroup analyses showed that the GG genotype EPHX1 rs2234922 was associated with increased plasma CBZ concentration in the Asian group (P = 0.005, I2 = 48.6%, Ph = 0.143). Conclusion EPHX1 rs1051740 T > C and rs2234922 A > G are important genetic variants associated with plasma CBZ concentration. The role of EPHX1 polymorphisms in the interindividual variability of plasma CBZ concentration varied significantly among different ethnic groups, which should be considered during clinical validation and in future studies.

Introduction This study was performed to explore the efficacy and safety of pregabalin and gabapentin in patients with spinal cord injury (SCI)-induced neuropathic pain to determine which treatment is most suitable for such patients. Methods We searched the PubMed, MEDLINE, Embase, and Cochrane Library databases from database inception to August 31, 2020. The quality of the included studies was assessed. We selected the average pain intensity after treatment and the proportion of patients who discontinued treatment because of adverse effects as the outcome indicators for efficacy and safety, respectively. Statistical analyses were performed using Stata, v16.0, and RevMan, v5.3, software. Results We included eight randomized controlled trials that examined four interventions (pregabalin, gabapentin, carbamazepine, and amitriptyline). Based on the average pain intensity after treatment, the efficacy order from highest to lowest was pregabalin, gabapentin, amitriptyline, carbamazepine, and placebo. Based on the proportion of patients who discontinued treatment because of adverse effects, the order from highest to lowest was pregabalin, amitriptyline, carbamazepine, gabapentin, and placebo. In addition, five studies reported the overall incidence of treatment-related adverse effects for two interventions (pregabalin and gabapentin). According to the pooled analysis of these studies, the order for the overall incidence of treatment-related adverse effects from highest to lowest was pregabalin, gabapentin, and placebo. Conclusions This study revealed that for patients with SCI-related neuropathic pain, pregabalin was the most effective for relieving pain, whereas gabapentin performed better in aspects associated with drug therapy-related safety. Supplementary Information The online version contains supplementary material available at 10.1007/s40122-021-00302-8.

Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition characterized by abnormal involuntary movements that are precipitated by a sudden movement. PKD is often misdiagnosed with psychogenic movement disorders. Carbamazepine is usually the first choice of medication due to its well-established evidence but could induce Stevens-Johnson syndrome. We report a 21-year-old male patient with PKD referred to our movement disorders clinic after being misdiagnosed with conversion syndrome. PRRT2 gene testing using next-generation sequencing revealed a mutation in c.649dupC p. (Arg217fs). The patient responded well to carbamazepine but had to withdraw the treatment due to carbamazepine-induced Stevens-Johnson syndrome after 3 weeks of medication. Our patient did not respond to trials of levetiracetam and phenytoin but finally responded well to oxcarbazepine. The patient was followed up for 4 years, during which he had no attacks and no side effects. Here, we present a PKD case with carbamazepine-induced Stevens-Johnson syndrome successfully treated with oxcarbazepine despite the risk of cross-reactive skin eruption between these antiepileptics. Careful history taking and examining patient’s attacks are crucial to accurate diagnosis and treatment in PKD patients.

Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute life threatening mucocutaneous drug reactions. Several therapies have been used in the treatment of SJS/TEN but none of them have been established as the gold standard treatment, until now. Studies showed that cyclosporine (CsA) can be used off-label in TEN/SJS and has shown promising therapeutic effectiveness in such diseases. Here we report a 38 year-old woman who presented to Ar Rustaq Hospital, Rustaq, Oman in 2019 with SJS/TEN overlap and was treated successfully with CsA along with supportive management. This case report also includes a literature review on use of CsA in the treatment of SJS/TEN. Keywords: Steven Johnson Syndrome; Toxic epidermal necrolysis; Epidermal necrolysis; cyclosporine; Drug eruption; case report; Oman

AIMS Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients. METHODS Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined. RESULTS Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs. CONCLUSION The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.

Objective: To compare the effectiveness of Carbamazepine versus Topiramate for the management of trigeminal neuralgia. Study Design: Comparative prospective study. Place and Duration of Study: Oral and Maxillofacial Surgery department, Allied Hospital, Faisalabad Pakistan, from Nov 2017 to Nov 2018. Methodology: A total of 60 patients (30 in each group) were included. Group A was treated with Carbamazepine 100mg TDS and group B with Topiramate 25mg TDS. Visual analogue scale was used to access pain and was calculated at 1st visit (baseline), at 7th day, at 14th day and at 28th day. Results: Out of 60 patients, mean of age was 54.78 ± 8.49 years. Right and left side of the face was involved in 41 (68.3%) and 19 (31.7%) patients respectively. Maxillary branch was involved in 24 (40%) and mandibular branch was involved in 36 (60%) patients. The mean of visual analogue scale after 7 days in group A was 4.53 ± 0.93 and in group B was 7.1 ± 1.07, after 14 days mean of visual analogue scale in group A was 3.7 ± 1.02 and in group B was 4.03 ± 1.27. Mean of visual analogue scale after 28 days in group A was 3.27 ± 1.01 3.93 ± 1.28. The results were statistically significant with p-value of 0.03. Conclusion: Topiramate has comparable efficacy as that of Carbamazepine at dose of 75-100mg with lesser side effects. So Topiramate can be used as first line of treatment in trigeminal neuralgia.

Introduction Glossopharyngeal neuralgia is a rare syndrome characterized by paroxysms of unilateral and severe stabbing pain occurring in the nerve’s distribution. Although other neuralgias are well described in the medical literature, glossopharyngeal neuralgia and its physiopathology are not. The vascular compression at the nerve root entry zone is the primary explanation for the disease. The first-line treatment is pharmacological, including carbamazepine, oxcarbazepine, and gabapentin. Surgical treatment is offered to medication-refractory patients, and microvascular decompression surgery has the best outcomes. Objective To investigate the pathophysiological and clinical aspects of the different presentations of glossopharyngeal neuralgia. Method: A systematic review of the literature including case reports and clinical trials, was done. Results A search of the literature yielded 31 papers that regarded glossopharyngeal neuralgia or its variants. Eight of these reports regarded vagoglossopharyngeal neuralgia. Seven regarded the glossopharyngeal neuralgia followed by or caused by another disease. Conclusion Glossopharyngeal neuralgia is a rare disease and requires further studies on its mechanism and clinical assessment; the physician needs to know how to distinguish it from its variants and underlying causes.

AIM: To conduct a retrospective comparative analysis of the efficacy and safety of epilepsy therapy with antiepileptic drugs. MATERIALS AND METHODS: The analysis of the treatment of 428 patients with epilepsy at the Children’s City Hospital No. 8 in Kazan, receiving antiepileptic drugs. RESULTS: It was found that valproic acid is more effective in the treatment of idiopathic generalized epilepsies compared to focal epilepsies ( p = 0.0006). Valproate and carbamazepine were the most effective in the treatment of focal epilepsy with short- and long-term follow-up. Valproic acid is more effective than topiramate ( p = 0.02), oxcarbazepine ( p = 0.003), and levetiracetam ( p = 0.003) in the treatment of focal epilepsy in short- and long-term follow-up. Carbamazepine is more effective than topiramate ( p = 0.01), oxcarbazepine ( p = 0.02), and levetiracetam ( p = 0.001) in the treatment of focal epilepsy in long-term follow-up. It was revealed that more often they complained about side effects when using carbamazepine (63.2%). Levetiracetam was found to be better tolerated compared to valproate ( p = 0.0006) and carbamazepine ( p = 0.0006). Topiramate is better tolerated than carbamazepine ( p = 0.02) and valproate ( p = 0.03). Oxcarbazepine is better tolerated than carbamazepine in women ( p = 0.04). CONCLUSIONS: When choosing an antiepileptic drug, it is necessary to be guided by the principle: first the basic, and then the drugs of the next generations, in the future, rely on information about the tolerability of the drug. It is necessary to evaluate the therapeutic effect of antiepileptic drugs with long-term observation, and use the criterion of “complete absence of seizures” as an indicator of the effectiveness of drugs.

Background:Caring for women with epilepsy (WWE) during pregnancy poses unique challenges. We conducted an audit of the care our epilepsy clinic provided to pregnant WWE.Methods:We performed a retrospective study on all pregnancies followed by an epileptologist at a Canadian tertiary care centre’s epilepsy clinic between January 2003 and March 2021. Among 81 pregnancies in 53 patients, 72 pregnancies in 50 patients were analyzed to determine patient-related, follow-up-related, antiseizure-medication-related, and child-related pregnancy characteristics. Univariate analyses were performed to explore if these characteristics were associated with disabling seizure occurrence during pregnancy.Results:Most pregnancies were intended (72%) and occurred in women who used folic acid pre-pregnancy (76%) and who followed recommended blood tests for antiseizure medication (ASM) levels (71%). In 49% of pregnancies, ASM dosage was modified; 53% of these modifications were made in response to ASM blood levels. Most often used ASMs were lamotrigine (43%), followed by carbamazepine (32%) and levetiracetam (13%). One child was born with a thyroglossal duct cyst; our congenital malformation rate was thus 2%. Disabling seizures occurred in 24% of pregnancies. Exploratory analyses suggested that disabling seizure occurrence during pregnancy was associated with younger patient age (p = 0.018), higher number of ASMs used during pregnancy (p = 0.048), lamotrigine usage in polytherapy (p = 0.008), and disabling seizure occurrence pre-pregnancy (p = 0.027).Conclusion:This Canadian audit provides an in-depth description of pregnancies benefiting from specialized epilepsy care. Our results suggest an association between disabling seizure occurrence during pregnancy and lamotrigine usage in polytherapy that warrants further evaluation.

Introduction The present evidence indicates that approximately 70% of patients with epilepsy can be successfully treated with antiepileptic drugs (AEDs). A significant proportion of patients are not under sufficient control and pharmacoresistant epilepsy is clearly associated with poor quality of life and increased morbidity and mortality. There is a great need for newer therapeutic options able to reduce the percentage of drug-resistant patients. Areas covered A number of hypotheses trying to explain the development of pharmacoresistance have been put forward. These include: target hypothesis (altered AED targets), transporter (overexpression of brain efflux transporters), pharmacokinetic (overexpression of peripheral efflux transporters in the intestine or kidneys), intrinsic severity (initial high seizure frequency), neural network (aberrant networks) and gene variant hypothesis (genetic polymorphisms). Expert opinion A continuous search for newer AEDs or among non-AEDs (blockers of efflux transporters, interleukine antagonists, cyclooxygenase inhibitors, mTOR inhibitors, angiotensin II receptor antagonists) may provide efficacious drugs for the management of drug-resistant epilepsy. Also, combinations of AEDs exerting synergy in preclinical and clinical studies (for instance, lamotrigine + valproate, levetiracetam + valproate, topiramate + carbamazepine) might be of importance in this respect. Preclinically antagonistic combinations must be avoided (lamotrigine + carbamazepine, lamotrigine + oxcarbazepine).

Neurocysticercosis (NCC) is a significant problem in India and other developing countries; however, several aspects of this disease have no clear, practical guidelines. There is a need for pragmatic guidelines, summarizing the available evidence, and filling in the gaps in evidence with expert advice to manage children with neurocysticercosis. An expert group (16 members) and a writing group (8 members) was constituted, consisting of members with varied expertise. It included pediatric neurologists (18), neurologist (1), Neuroradiologists (4), and a parasitologist (1). The writing group divided the six topics and reviewed the literature on the topics individually to determine the clinical questions for which no clear guidance was available from the literature. The experts were then contacted and opinions were obtained online. The Delphi consensus method was adopted to arrive at a general consensus regarding various questions, with both the experts and the writing group members contributing. The final guidelines were then drafted by the writing group. Diagnosis of NCC should be based on clinical history and neuroimaging. Contrast-enhanced magnetic resonance imaging of the brain is the modality of choice. For single enhancing lesion, albendazole therapy for 10–14 days is recommended, and it should be combined with praziquantel for 10–14 days for more than one ring-enhancing lesions. For persistent lesion, the same dose and duration of albendazole or concurrent administration of albendazole and praziquantel should be given. Pulse intravenous steroids should be used to reduce the acute symptomatic edema in children with cysticercal encephalitis. Carbamazepine or oxcarbazepine are best suited for seizure prophylaxis for those who present with seizures; phenytoin and levetiracetam are the other alternatives. In the case of NCC presenting with symptoms other than seizures, there appears to be no role for routine anti-seizure medication prophylaxis. For a single ring-enhancing lesion, six months of anti-seizure medication is sufficient if the lesion resolves on follow-up. Those with persistent lesions, calcification, or multiple lesions, require a longer treatment duration of at least 24 months.

Pharmacodynamic aggravation (PA) is an unpredictable increase in the frequency, the severity of existing seizures, and/or development of new seizure types despite rational (adequate for seizure type and epilepsy form) antiepileptic drug (AED) prescription. Many mechanisms and predictors of its development are still poorly understood.Objective: to analyze PA of seizures in patients with newly diagnosed focal epilepsy receiving monotherapy with sodium channel blockers with epileptiform activity index (EAI) assessment.Patients and methods. We enrolled 201 patients with newly diagnosed focal epilepsy aged 16—81 years. In twelve months, patients had five follow-up visits. At each visit, treatment tolerability and efficacy were assessed, taking into account changes in the type, severity, and frequency of seizures. Additionally, at each visit, video-electroencephalographic monitoring was performed with EAI assessment. PA of seizures occurred in patients on oxcarbazepine, carbamazepine, and lacosamide therapy.Results and discussion. Five patients with PA of seizures had increased total EAI and EAI before sleep at the second follow-up visit after sodium channel blockers prescription. Electroencephalographic correlates of PA occurred earlier than clinical manifestations. In patients with PA, the absolute increase in EAI was minimal in patients receiving oxcarbazepine, and lacosamide therapy was associated with a minimal relative increase in EAI. At the end of the follow-up, total EAI decreased by 54—80% relative to its initial value in all five patients. The difference in the total index during the first and last visits was statistically significant.Conclusion. Due to the low level of knowledge about PA of seizures, it seems necessary to consider its possibility in all cases of increased frequency, aggravation, or change in the type of seizures after the AED treatment initiation or an increase in its dose. It is also possible to use changes in total EAI and EAI before sleep as an early objective marker of PA in adults with focal epilepsy.

To assess vitamin D status of children on long-term anticonvulsants, including the less studied widely used levetiracetam, and the potential risk factors for deficiency. Children on antiepileptic drugs (cases, n = 269) were compared with controls (n = 295) for serum biochemistry, 25OHD, parathormone (PTH), sun exposure, dietary calcium, and vitamin D intake. Cases had lower serum 25OHD [median (IQR) 18.4 (11.5–24.1) ng/mL] compared to controls [20.8 (15.4–26.2] ng/mL, p < 0.001), as well as more frequent vitamin D deficiency (25OHD < 12 ng/mL, 27.1%) and insufficiency (25OHD < 20 ng/mL, 57.6%) than did controls (11.2% and 46.1%, respectively). Significantly lower median (IQR) serum calcium [8.8 (8.1–9.4) vs. 9.2 (8.5–10.0) mg/dL], phosphorous [3.8 (3.3–4.2) vs. 4.7 (4.0–5.3) mg/dL), and higher PTH [58.4 (42.9–85.8) vs. 38.9 (24.6–55.5) pg/mL, p < 0.001 for all] and proportion of elevated alkaline phosphatase (11.2% vs. 5.1%, p < 0.01) was seen in cases versus controls. Vitamin D deficiency was present in 53.4% of children with cerebral palsy (CP) versus 19.9% in those without CP (p < 0.001). Serum 25OHD did not differ between patients on cytochrome P450 inducers versus noninducers, neither among the 3 major groups, users of carbamazepine, valproate, and levetiracetam. Logistic regression analysis showed serum 25OHD < 12 ng/mL to be independently influenced by case or control status, presence of CP, and season of sampling. Vitamin D deficiency is common with anticonvulsant therapy, especially in those having CP. In Kerala, the hot, dry season from March to May is protective.

Background Antiseizure drugs (ASDs) are the primary therapy for epilepsy, with more than 20 drugs introduced into clinical practice to date. These drugs are typically grouped by their mechanisms of action and therapeutic spectrum. This article aims to educate non‐neurologists and medical students about the new frontiers in the pharmacology of ASDs and presents the current state of the literature on the efficacy and tolerability of these agents. Methods Randomized controlled trials, observational studies, and evidence‐based meta‐analyses of ASD efficacy and tolerability as initial monotherapy for epileptic seizures and syndromes were identified in PubMed, EMBASE, the Cochrane Library, and Elsevier Clinical Pharmacology. Results The choice of ASD varies primarily according to the seizure type. Practical guidelines for ASD selection in patients with new‐onset and drug‐resistant epilepsy were recently published. The guidelines have shown that the newer‐generation drugs, which have unique mechanistic and pharmacokinetic properties, are better tolerated but have similar efficacy compared with the older drugs. Several ASDs are effective as first‐line monotherapy in focal seizures, including lamotrigine, carbamazepine, phenytoin, levetiracetam, and zonisamide. Valproate remains the first‐line drug for many patients with generalized and unclassified epilepsies. However, valproate should be avoided, if possible, in women of childbearing potential because of teratogenicity. Toxicity profile precludes several drugs from use as first‐line treatment, for example, vigabatrin, felbamate, and rufinamide. Conclusions Antiseizure drugs have different pharmacologic profiles that should be considered when selecting and prescribing these agents for epilepsy. These include pharmacokinetic properties, propensity for drug‐drug interactions, and adverse effects., Antiseizure drugs (ASDs) have many different pharmacologic profiles that are relevant when selecting and prescribing these medications in patients with epilepsy. Some second‐generation ASDs have shown advantages in drug tolerability, drug‐drug interactions, and teratogenicity. Disappointingly, however, none of these medications appear to be more efficacious than first‐generation ASDs.

Aims To characterize the population pharmacokinetics of lamotrigine in Jordanian epileptic patients and to identify factors affecting therapeutic parameters. Patients and Methods A population pharmacokinetics model for lamotrigine was established based on a prospectively collected data of 52 steady-state concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine concentrations were determined by a dried blood spot liquid chromatography method. Data were analyzed according to a one-compartment model with first-order absorption and elimination using the nonlinear mixed effect modeling program. The covariates effect of total body weight, gender, age, and co-medication with topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on lamotrigine clearance were investigated using a stepwise forward addition followed by a stepwise backward elimination. Results The final population pharmacokinetics model for lamotrigine clearance was as follows: CL/Fpop=θ1*exp (θ3*age)*exp (θ5*carbamazepine)*exp (θ6*valproic acid) , where θ1 is the relative clearance (L/hr) estimated, and θ3, θ5, and θ6 are the fixed parameters relating to age and co-medication with carbamazepine and valproic acid, respectively.The population mean value of lamotrigine total clearance generated in the final model (with covariates) was 2.12 L/hr. Inter-individual variability and residual unexplained variability expressed as the coefficient of variation was 37.1 and 26.1%, respectively. Conclusion Lamotrigine total clearance in the Jordanian patients is comparable to that reported by others for Caucasian patients. Age and concomitant therapy with carbamazepine and valproic acid significantly affected lamotrigine clearance, and accounted for 48% of its inter-individual variability.

Electroencephalography (EEG) remains an important investigative tool in supporting the diagnosis and classification of various seizure types. We sought to examine and characterize the EEG findings from all patients referred for the procedure. This cross-sectional retrospective study was carried out at an EEG unit in Federal Medical Centre, Makurdi, Benue State, North Central Nigeria from May 2016 to December 2020. Relevant patients' information were extracted and analysed using SPSS version 21. A total of 484 patients were seen over the study period with age range of 1-87 years and median age of 23 years. They comprised of 254 (52.5%) male and 230 (47.5%) female. The psychiatrist and the Physicians/Neurologist referred most of them for EEG, 201 (41.5%) and 124 (25.6%) respectively. The most reported indication for EEG was clinical suspicion of seizure disorder 291 (60.1%), whilst some did not have a clear indication 111 (22.9%). About 417 (86.2%) of our patients had abnormal EEG finding out of which 414 (99.3%) were diagnostic of seizure disorder made up of generalized seizure in 255 (61.6%) and focal seizure in 159 (38.4%). About 237 (48.9%) of them were already on antiepileptic drugs (AEDs) at referral of which 190 (80.2%0 were taking carbamazepine. This study showed a high prevalence of abnormal EEG with most of them diagnostic of seizure disorder especially generalized seizure. They were mostly of younger age group with about half of them already on AEDs at referral, majority of who were sent by the Psychiatrist.

Aim: This study evaluated the hepatotoxicity and lipid profiles of male Wistar rats following chronic carbamazepine (CBZ), gabapentin (GBP) and carbamazepine-gabapentin (CBZ+GBP) adjunctive treatment. Methods: Twenty-eight male Wistar rats were randomized into 4 groups (n = 7) to receive daily oral administration of normal saline (0.2ml), or CBZ (25 mg/kg), or GBP (50 mg/kg), or the sub-therapeutic dose of CBZ (12.5 mg/kg) and GBP (25 mg/kg) combination for 56 days. Thereafter, blood and liver homogenate were subjected to biochemical analysis, while liver tissues were processed for the histomorphological investigation. Data were analysed statistically, while p< 0.05 was taken as level of significance. Results: Activities of alanine phosphatase and aspartate aminotransferase significantly increased in the CBZ and CBZ + GBP treated rat. CBZ and CBZ + GBP treatments increased the plasma concentration of low-density lipoprotein and total cholesterol. The liver concentration of malondialdehyde increased significantly in all the treated groups relative to control. There were severe vascular congestions in theliver of the CBZ treated rats, this was moderate in the GBP and CBZ + GBP treated rats. Conclusion: Chronic use of CBZ may induce hepatotoxicity and lipid profile derangement, GBP and CBZ + GBP adjunctive treatment may be saver than treatment with CBZ.