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We describe a man in his 30s who presented with paroxysmal right-sided dyskinesias of the arm and neck, misdiagnosed with drug-resistant focal epilepsy. Two months earlier he had undergone surgery for chronic sinusitis. Immediately after this procedure, he developed hemiparesis, hemiataxia, paresthesias and disturbances in verbal fluency. Cranial MRI revealed a disruption of the left lamina cribrosa and an intracerebral injury resembling a branch canal spanning to the left dorsal third of the thalamus. Single-photon emission tomography imaging demonstrated malperfusion of the left ventral thalamus, left-sided cortex and right cerebellar hemisphere. During continuous video-EEG monitoring, three dyskinetic episodes with tremor of the right arm and dystonia of the finger and shoulder could be recorded. The paroxysmal dyskinesias did not improve with carbamazepine, valproate and tiapride. This case demonstrates an unusual symptomatic cause of a thalamic movement disorder misdiagnosed as focal epilepsy and highlights the postoperative complications, diagnostic and treatment efforts.

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.

For bipolar disorder, a severe, recurring mental disorder, pharmacotherapy is a cornerstone of effective treatment. The purpose of this study was to investigate prescribing changes among patients with bipolar disorder discharged from two public psychiatric hospitals in Taiwan over a 14-year period.Patients with bipolar disorder discharged from the two study hospitals between 2006 and 2019 (n = 9071) were included in the analysis. Prescribed drugs for the treatment of bipolar disorder, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), any antipsychotics (i.e., second- and first-generation antipsychotics; SGAsFGAs), and any antidepressants, were examined. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test.The prescription rates of SGAs, any antidepressants, antidepressant monotherapy, antidepressants without mood stabilizers, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, lithium, carbamazepine, FGAs, and antidepressants plus mood stabilizers significantly decreased.Treatment allocation is not randomized in a retrospective study. The diagnoses of bipolar disorder were based on clinical judgments. This was a hospital-based study.Substantial prescribing changes took place during the study period. The decreased use of lithium and the increased use of antidepressants were not in accordance with the evidence-based treatment and recommendations in treatment guidelines. Therefore, long-term outcomes of prescribing changes should be explored in the future.

Rivaroxaban (RIV; Xarelto; Janssen Pharmaceuticals, Beerse, Belgium) is one of the direct oral anticoagulants. The drug is a strong substrate of cytochrome P450 (CYP) enzymes and efflux transporters. This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for RIV. It contained three hepatic metabolizing enzyme reactions (CYP3A4, CYP2J2, and CYP-independent) and two active transporter-mediated transfers (P-gp and BCRP transporters). To illustrate the performance of the developed RIV PBPK model on the prediction of drug-drug interactions (DDIs), carbamazepine (CBZ) was selected as a case study due to the high DDI potential. Our study results showed that CBZ significantly reduces the exposure of RIV. The area under the concentration-time curve from zero to infinity (AUC

In times of severe antiseizure medication (ASM) shortage due to emergency situations (e.g., disasters, conflicts, sudden disruption to international supply chains), management of people with epilepsy with available ASMs can be difficult. A group of experts was brought together by the International League Against Epilepsy (ILAE) to formulate recommendations for such circumstances. Every effort was made to base these recommendations on direct published literature or extrapolations from basic information available about ASMs. Actual published literature in this area is, however, limited, and at times, assumptions were made by the experts to generate these recommendations. During times of shortage of ASMs, switching between different ASMs (e.g., oxcarbazepine and carbamazepine) can occasionally be considered as a mitigation procedure. However, for many ASMs, the option of an overnight switch to another drug does not exist. Switching from brand to generic or between generic products has often been shown to be safe, if required. Finally, when supplies of benzodiazepines or equipment to administer medications intravenously are not available, rectal administration of some ASMs may be an emergency alternative route for treating serial seizures and status epilepticus. Decision-making with regard to treatment and possible options should be driven by what is best for the patient.

Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor. In the light of applying the DDI-Predictor, for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.

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.

This study aimed to investigate the factors affecting the plasma concentration of monohydroxylated derivative (MHD) of oxcarbazepine (OXC) in children with epilepsy.We recruited 125 children with epilepsy who received OXC monotherapy. Among them, 16 single nucleotide polymorphisms were detected by MassARRAY genotyping technology to evaluate the influence of related factors on the plasma concentration of OXC monotherapy. MHD is the main active metabolite of OXC, and its plasma concentration was measured by high-performance liquid chromatography (HPLC).Bivariate correlation analysis revealed that concentration-dose ratio (CDR) increased with weight, and the corresponding maintenance dose decreased with weight (r=0.317, P=0.001 for CDR; r=-0.285, P=0.000 for OXC maintenance dose). The duration of seizure was found to be associated with CDR (0.90 ± 0.36 vs 0.74 ± 0.26 μg·kg/mg/mL for ≥6 years vs1 year, P=0.028; 0.90 ± 0.36 vs 0.64 ± 0.21 μg·kg/mg/mL for ≥6 years vs 1-3 years, P=0.004; 0.90 ± 0.36 vs 0.69 ± 0.18 μg·kg/mg/mL for ≥6 years vs 3-6 years, P=0.031). The CDR of patients with ABCB1 rs1045642 mutation homozygous GG type is higher than heterozygous AG type (0.79 ± 0.30 vs 0.68 ± 0.20 μg·kg/mg/mL for AG vs GG, P=0.032).This study clarified the association of weight, duration of seizure, and gene polymorphisms of ABCB1 rs1045642 with MHD plasma concentration in children with epilepsy.

Rat isolated vas deferens releases 6-nitrodopamine (6-ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the αsub1/sub-adrenergic receptors such as doxazosin, tamsulosin, and prazosin.To investigate the liberation of 6-ND by human epididymal vas deferens (HEVDs) and its pharmacological actions.The in vitro liberation of 6-ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC-MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric-field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L-NAME and the release of catecholamines and the contractile response to EFS were assessed.6-ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6-ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L-NAME reduced both the 6-ND release and the contractions induced by EFS.6-ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and αsub1/sub-adrenergic receptor antagonists.

To investigate the effects of tegretol on oxidative stress, serum inflammatory factors, and left ventricular function in patients with acute myocardial infarction (AMI) after emergency percutaneous coronary intervention (PCI), 70 AMI patients who received PCI in the emergency department of our hospital from January 2021 to December 2021 were collected. The patients in the control group were treated with aspirin, clopidogrel, and heparin sodium during the perioperative period, and the patients in the study group were treated with tegretol. The levels of oxidative stress, serum inflammatory factors, and left ventricular function index were compared between the two groups. The patients in the control group were treated with TT (( 12.00 ± 2.05 ) s), APTT (( 35.50 ± 4.19 ) s), PT (( 16.60 ± 1.58 ) s), TT (( 15.90 ± 2.14 ) s) APTT (( 30.40 ± 3.80 ) s), and PT (( 14.30 ± 1.45 ) s)) and were comparable ( P > 0.05 ), and the difference was statistically significant ( t = 8.210 , 4.600, 7.010, P < 0.001 ). There was no comparable difference in the level of oxidative stress index before treatment ( P > 0.05 ). After treatment, there was significant difference in MDA (( 14.53 ± 2.14 ) mmol/L), SOD (( 120.45 ± 8.17 ) U/L), MDA (( 11.15 ± 2.02 ) mmol/L), and SOD (( 129.86 ± 8.55 ) U/L) in the control group ( t = 7.320 , 5.099, P < 0.001 ). The levels of inflammatory factors in patients before treatment were not comparable ( P > 0.05 ). After treatment, there were levels of IL-6 (( 3.20 ± 1.05 ) ng/L), CRP (( 4.80 ± 1.16 ) mg/L), MPO (( 196.78 ± 21.51 ) mg/L) and TNF-α (( 3.96 ± 0.80 ) pmol/L), IL-6 (( 1.95 ± 0.80 ) ng/L), CRP (( 3.10 ± 1.02 ) mg/L), MPO (( 163.60 ± 21.10 ) mg/L), and TNF-α in a study group level (( 3.05 ± 0.70 ) pmol/L), with statistically significant difference ( t = 5.187 , 6.028, 6.031, 4.689, P < 0.001 ). Before treatment, there was no comparable difference in the level of left ventricular function index ( P > 0.05 ). After treatment, there was significant difference in LVEF ((46.10 ± 2.39) %) and LVDD ((52.06 ± 1.07) mm), LVEF ((56.85 ± 2.33) %), and LVDD ((48.75 ± 1.02) mm) in the control group ( t = 17.640 , 21.540, P < 0.001 ). Tegretol as an adjunctive therapy for emergency PCI patients with acute myocardial infarction can effectively improve postoperative coagulation function, reduce oxidative stress and inflammatory reaction, and improve cardiac function indicators. It has a positive clinical value.

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.

Paroxysmal dystonia occurs because of genetic or structural lesion in the basal ganglia or thalamus, and there is paucity of reporting in spinal pathology. We report a patient with paroxysmal hemidystonia admitted to a tertiary care hospital, India, and review the literature on spinal dystonia in neuromyelitis optica (NMO). A 19-year-old woman presented with recurrent visual loss and quadriparesis. She developed paroxysmal hemidystonia after 18 days of a second episode of quadriplegia, during which her muscle power improved to Grade 3. Magnetic resonance imaging (MRI) of her spine showed central T2 hyperintensity extending from C2 to C7 vertebral level, and a cranial MRI was normal. Tibial somatosensory evoked potentials were unrecordable. Aquaporin-4 antibody was positive in serum, confirming the diagnosis of NMO. Paroxysmal hemidystonia responded to carbamazepine 200 mg thrice daily. Paroxysmal dystonia may occur in a patient with myelitis and may respond to carbamazepine.

The concentrations and distribution of β-blockers, lipid regulators, and psychiatric and cancer drugs in the influent and effluent of the municipal wastewater treatment plant (WWTP) and the effluent of 16 hospitals that discharge into the wastewater treatment plant mentioned in this study at two sampling dates in summer and winter were examined. The pharmaceutical contribution of hospitals to municipal wastewater was determined. The removal of target pharmaceuticals was evaluated in a WWTP consisting of conventional biological treatment using activated sludge. Additionally, the potential environmental risk for the aquatic receiving environments (salt lake) was assessed. Beta-blockers and psychiatric drugs were detected in high concentrations in the wastewater samples. Atenolol (919 ng/L) from β-blockers and carbamazepine (7008 ng/L) from psychiatric pharmaceuticals were detected at the highest concentrations in hospital wastewater. The total pharmaceutical concentration determined at the WWTP influent and effluent was between 335 and 737 ng/L in summer and between 174 and 226 ng/L in winter. The concentrations detected in hospital effluents are higher than the concentrations detected in WWTP. The total pharmaceutical contributions from hospitals to the WWTP in summer and winter were determined to be 2% and 4%, respectively. Total pharmaceutical removal in the WWTP ranged from 23 to 54%. According to the risk ratios, atenolol could pose a high risk (risk quotient10) for fish in summer and winter. There are different reasons for the increase in pharmaceutical consumption in recent years. One of these reasons is the COVID-19 pandemic, which has been going on for 2 years. In particular, hospitals were operated at full capacity during the pandemic, and the occurrence and concentration of pharmaceuticals used for the therapy of COVID-19 patients has increased in hospital effluent. Pandemic conditions have increased the tendency of people to use psychiatric drugs. It is thought that beta-blocker consumption has increased due to cardiovascular diseases caused by COVID-19. Therefore, the environmental risk of pharmaceuticals for aquatic organisms in hospital effluent should be monitored and evaluated.

The worldwide occurrence of pharmaceuticals and personal care products (PPCPs) in aquatic ecosystems is reason for concern, since these emerging micro pollutants, includes a large and diverse group of organic compounds, with continuous input, high environmental persistence and potential threat to biota and human health. The aim of this study was to evaluate, for the first time, the occurrence of twenty-seven PPCPs of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine), in the coastal waters of Santa Catarina, southern Brazil. Water samples were taken in November 2020, during the low tide periods, at eight sampling points located along the coast of Santa Catarina, covering its entire geographical extension. Sampling was carried out in triplicate and at different depths of the water column. Nine compounds were detected through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS): caffeine (12.58-119.80 ng/L), diclofenac (1.398-7.920 ng/L), losartan (0.432-3.200 ng/L), cocaine (0.0248-0.1686 ng/L) and benzoylecgonine (0.0146-1.094 ng/L) were quantified in 100% of the samples; carbamazepine (0.0242-0.2720 ng/L) was quantified in 75% of the samples; acetaminophen (0.212-10.040 ng/L) was quantified in 60% of the samples; and both atenolol (1.13-2.50 ng/L) and orphenadrine (0.073-0.0886 ng/L) were quantified in 25% of the samples. The other PPCPs were below the limit of detection (LOD). The highest occurrence of these compounds was detected in the northern and central coastal region of Santa Catarina, namely in Penha and Palhoça cities. The sources of these compounds may be associated with areas with high population density, awaited by tourism, with consequent production of sanitary sewage and solid waste. The ecological risk assessment of these substances in the aquatic ecosystems showed that 67% and 77% of the compounds respectively presented no ecological risk, acute and chronic, but 44% presented low to moderate risks for acute and chronic effects in the three trophic levels evaluated. The occurrence of these chemical compounds can imply deleterious effects on the environmental health of Santa Catarina coastal zone, and therefore deserve more acute and directed attention.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe adverse drug reaction generally accompanied by skin manifestations as the first and most frequent symptoms. However, skin manifestations and associated clinical features of DRESS have not been fully explored and evaluated.This study aimed to describe the skin manifestations of DRESS in detail and analyse their association with demographic characteristics and extra-cutaneous clinical features.We conducted this retrospective study on patients with DRESS diagnosed between September 2009 and August 2021 at three medical institutes and validated using the RegiSCAR score. Data regarding demographics, skin manifestations and clinical characteristics were retrieved through thorough chart reviews.Among 182 potential cases of DRESS, the validated 125 cases were analysed. A widespread rash extending over more than 50% of the body surface area was observed in 122 patients (97.6%) and typical facial oedema was experienced by 67 patients (53.6%). Polymorphous maculopapules were the most common rash morphology (106, 84.8%): specifically, exfoliative (59, 47.2%), urticarial (57, 45.6%) and purpuric forms (39, 31.2%) were common. Mucosal involvement was observed in 41 patients (32.8%). Patients with carboxamide antiepileptics (carbamazepine and oxcarbazepine) experienced more oedema (P = 0.014) and typical facial oedema than those with allopurinol (P = 0.021). The RegiSCAR score was higher in patients with purpura (P 0.01).Skin manifestations of DRESS exhibit a wide range of skin lesions and can vary according to the culprit drugs. Early suspicion and prompt intervention are needed to improve prognosis.

Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) is widely used to guide therapy, avoid toxicity, and assess patient compliance. Commercial immunologic quantification methods are common practice; however, as they are only applicable to one specific drug and prone to cross-reacting metabolites, their practical applicability is limited. In this article, the authors proposed a high-performance liquid chromatography method using ultraviolet detection (HPLC-UV) for simultaneous quantification of 11 ASMs and active metabolites (carbamazepine, felbamate, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, zonisamide, carbamazepine-10,11-epoxide, and licarbazepine) in serum.Chromatographic separation was performed on a Phenomenex Luna PFP(2) (3-µm particle size; 150 × 4.6 mm i.d.) analytical column. The mobile phase comprised phosphate buffer (20 mM; pH 3), acetonitrile (ACN), and methanol using gradient elution. Analyses were conducted at 35°C and a 1.3-mL/min flow rate. The detection wavelength for all analytes was 210 nm. The samples were prepared by protein precipitation using ACN.The HPLC-UV method was validated according to the FDA guidelines and applied to measure patient samples in TDM. Calibration curves showed excellent linearity (r20.99) and covered the entire reference range for each analyte. Intraday and interday imprecisions and inaccuracies were10% for all samples. Extensive stability testing showed no significant degradation (15%), and interference measurements additionally ensured clinical applicability. Furthermore, the sensitivity was comparable with that of previously published HPLC methods using mass spectrometry.The authors developed an HPLC-UV method for the simultaneous quantification of 11 ASMs in the human serum and demonstrated its practical applicability in TDM. The method requires only standard laboratory equipment and simple sample preparation, making TDM available in less specialized laboratories.

Olfactory dysfunction is reported frequently in patients with coronavirus disease 2019. However, an effective treatment for this dysfunction is unknown. The present study evaluated carbamazepine as a treatment option for olfactory dysfunction based on its use in cases of neuralgia, especially of the V cranial nerve. The study included 10 patients with coronavirus disease with olfactory complaints who were part of a cohort of 172 coronavirus disease patients monitored for late neurological manifestations. Carbamazepine was administered for 11 weeks. The adverse effects reported were drowsiness (9/10) and dizziness (2/10); 9 of the 10 patients reported improved olfactory function after carbamazepine treatment. While the role of carbamazepine in the control of post-coronavirus disease olfactory dysfunction could not be confirmed in this study, the satisfactory response observed in most patients in this series suggests that further studies are warranted.

"Wealth by the sea and poverty away from the sea breeze" is a metaphor that mirrors what happens along the Brazilian coastal zone, namely in São Vicente Island, São Paulo, Brazil. Due to the high cost of the properties on this shore, the impoverished population started to migrate to the northern outskirts of the island (away from the tourist beaches), potentiating the emergence of poor housing conditions, namely stilt-house slums. Consequently, the urban drainage channels across these outskirts neighbourhoods are potentially contaminated by human wastes. In this context, the occurrence and preliminary ecological risk assessment of eleven pharmaceuticals of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine) were investigated, for the first time, in five urban drainage channels whose diffuse loads flow continuously to the estuarine waters of São Vicente Island. The results showed the widespread presence of these environmental stressors in all urban channels analysed, namely losartan (7.3-2680.0 ng/L), caffeine (314.0-726.0 ng/L), acetaminophen (7.0-78.2 ng/L), atenolol (6.2-23.6 ng/L), benzoylecgonine (10.2-17.2 ng/L), furosemide (1.0-7.2 ng/L), cocaine (2.3-6.7 ng/L), carbamazepine (0.2-2.6 ng/L), diclofenac (1.1-2.5 ng/L), orphenadrine (0.2-1.1 ng/L) and chlortalidone (0.5-1.0 ng/L). The overall total estimated load of pharmaceuticals and personal care products flowing to the estuarine waters of São Vicente Island is on the order of 41.1 g/day. The ecological risk assessment revealed a great environmental concern for São Vicente Island, ranging between low (e.g. carbamazepine and cocaine) and moderate to high (e.g. caffeine, acetaminophen and losartan) threats for the aquatic biota. Therefore, initiatives promoting basic sanitation, land-use regularisation and population awareness are highly recommended.

The literature on positive patch test results in drug reaction with eosinophilia and systemic symptoms (DRESS) is reviewed. One hundred and five drugs were identified that have together caused 536 positive patch tests in 437 DRESS patients. By far, the most reactions (n = 145) were caused by carbamazepine, followed by amoxicillin, isoniazid, phenytoin, ethambutol, fluindione, phenobarbital, rifampicin, and ceftriaxone; 43 drugs each caused a single case only. The drug classes causing the highest number of reactions were anticonvulsants (39%), beta-lactam antibiotics (20%), antituberculosis agents (11%), non-beta-lactam antibiotics (6%), and iodinated contrast media (5%). The sensitivity of patch testing (percentage of positive reactions) is high for anticonvulsants (notably carbamazepine), beta-lactam antibiotics (notably amoxicillin), and, possibly, iodinated contrast media. Allopurinol and sulfasalazine frequently cause DRESS but never give positive patch tests. Patch testing in DRESS appears to be safe, although mild recurrence of DRESS symptoms, mostly skin reactions, may not be rare. Multiple drug hypersensitivity was found to occur in 16% of all patients, but it is argued that the true frequency is higher. Clinical aspects of DRESS, including diagnosing the disease and identifying culprit drugs (patch tests, intradermal tests, in vitro tests, challenge tests) are also provided, emphasizing the role of patch testing.

Despite a dramatic increase in treatment options over the past 30 years, Carbamazepine (CBZ) is still considered the standard of care and the most prescribed initial treatment for focal epilepsy. Hence, the identification of genetic biomarkers that influence the response, resistance and toxicity to CBZ remains a challenge. Several research studies have looked into this to highlight the polymorphisms responsible for the variability in the response to CBZ in patients with epilepsy. The aim of this review is to compare the different results published in the literature The systematic review included thirty-nine studies (2005-2021), Meta-analyses were performed on more than twelve polymorphisms in three genes (ABCB1, ABCC2, RALBP1) involved in CBZ cell transport. The current challenges are to identify other new biomarkers of antiepileptic drugs that can only materialize with large-scale collaborative research efforts.

As a chronic brain disease, epilepsy affects ~50 million people worldwide. The traditional antiepileptic drugs (AEDs) are widely applied but showing various problems. Although the new AEDs have partially solved the problems of traditional AEDs, the current clinical application of traditional AEDs are not completely replaced by new drugs, particularly due to the large individual differences in drug plasma concentrations and narrow therapeutic windows among patients. Therefore, it is still clinically important to continue to treat patients using traditional AEDs with individualized therapeutic plans. To date, our understanding of the molecular and genetic mechanisms regulating plasma concentrations of AEDs has advanced rapidly, expanding the knowledge on the effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of AEDs. It is increasingly imperative to summarize and conceptualize the clinical significance of recent studies on individualized therapeutic regimens. In this review, we extensively summarize the critical effects of genetic polymorphisms of genes encoding drug-metabolizing enzymes on the plasma concentrations of several commonly used AEDs as well as the clinical significance of testing genotypes related to drug metabolism on individualized drug dosage. Our review provides solid experimental evidence and clinical guidance for the therapeutic applications of these AEDs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Antiseizure medications (ASMs) with aromatic ring structure, including carbamazepine, are among the most common culprits. Screening for human leukocyte antigen (HLA) allele HLA-B*15:02 is recommended prior to initiating treatment with carbamazepine in Asians, but this allele has low positive predictive value.We performed whole genome sequencing and analyzed 6 199 696 common variants among 113 aromatic ASM-induced SJS/TEN cases and 84 tolerant controls of Han Chinese ethnicity.In the primary analysis, nine variants reached genome-wide significance (p 5e-08), one in the carbamazepine subanalysis (85 cases vs. 77 controls) and a further eight identified in HLA-B*15:02-negative subanalysis (35 cases and 53 controls). Interaction analysis between each novel variant from the primary analysis found that five increased risk irrespective of HLA-B*15:02 status or zygosity. HLA-B*15:02-positive individuals were found to have reduced risk if they also carried a chromosome 12 variant, chr12.9426934 (heterozygotes: relative risk = .71, p = .001; homozygotes: relative risk = .23, p .001). All significant variants lie within intronic or intergenic regions with poorly understood functional consequence. In silico functional analysis of suggestive variants (p5e-6) identified through the primary and subanalyses (stratified by HLA-B*15:02 status and drug exposure) suggests that genetic variation within regulatory DNA may contribute to risk indirectly by disrupting the regulation of pathology-related genes. The genes implicated were specific either to the primary analysis (CD9), HLA-B*15:02 carriers (DOCK10), noncarriers (ABCA1), carbamazepine exposure (HLA-E), or phenytoin exposure (CD24).We identified variants that could explain why some carriers of HLA-B*15:02 tolerate treatment, and why some noncarriers develop ASM-induced SJS/TEN. Additionally, this analysis suggests that the mixing of HLA-B*15:02 carrier status in previous studies might have masked variants contributing to susceptibility, and that inheritance of risk for ASM-induced SJS/TEN is complex, likely involving multiple risk variants.

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: Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. Methods: The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. Results: Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. Conclusion: The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

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.

Ascorbyl palmitate is a fat-soluble ester of vitamin C and is used as an antioxidant food additive. While literature reports that ascorbyl palmitate can prevent exacerbation of pain and improve the quality of life of patients suffering from pain, this is not yet supported by clinical trial data. Our study aimed to investigate the effectiveness of ascorbyl palmitate in managing trigeminal neuralgia.This study was carried out in a single-centre clinical trial in which subjects suffering from trigeminal neuralgia (N=11) were included. All patients were on carbamazepine when first included and, after washout period, received Ascorbyl palmitate. Eligible patients had the most severe trigeminal neuralgia pain in the oral cavity or pain on touching trigger zones, aged 20 years or older, were capable of proper assessment of the severity of pain and their condition, and had experienced multiple episodes of intraoral pain for at least 3 months with a pain intensity of more than 4 points on the numerical rating scale. The Brief Pain Questionnaire was used to evaluate patient's quality of life.A total of 11 patients were included with a mean age 55.36±10.67 years (7 males, 4 females). Most patients had compression by the superior cerebellar artery and vascular loops upon magnetic resonance examination. The mean numerical rating scale score for carbamazepine after one month was 7.9±0.56 (95% CI 7.49, 8.30). Similarly, for ascorbyl palmitate was 5.5±1.50 (95% CI 4.42, 6.57) (p0.001).Ascorbyl palmitate can be used as an adjunct intervention in managing trigeminal neuralgia pain. According to the results, ascorbyl palmitate prevents frequent exacerbation of pain and improves patient quality of life.

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

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.

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.

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.

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.

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.

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.

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.

Although epilepsy is a common neurological condition, there is paucity of nationwide data on treatment patterns and sociodemographic and clinical factors affecting treatment decisions in India.To assess clinical profiles, usage pattern of antiepileptic drugs (AEDs), and seizure control among patients with epilepsy in India.This was a cross-sectional, observational, multicenter study on adult patients with epilepsy who were on AEDs for at least six months before enrollment. Data were collected from patient interviews and medical records.Out of 800 enrolled patients, a majority (69.0%) had generalized onset seizure in the six months before enrollment. The median age at epilepsy onset was 20.0 (1.0-64.0) years; 40.0% of the patients were females, 48.5% were married, 99.1% were literate, and 67.0% belonged to the lower or upper-middle socioeconomic class. Overall, 459 patients (57.4%) received AEDs as combination therapy. Most patients received levetiracetam (37.0%), sodium valproate (18.5%), carbamazepine (17.3%), or phenytoin (13.8%) as monotherapy, and clobazam (59.7%), levetiracetam (52.9%), carbamazepine (26.4%), sodium valproate (24.8%), or phenytoin (24.0%) in combination therapy. Quality of life was comparable for first- and third-generation AEDs. Adverse drug reactions were mostly attributed to dose modification or switching between drugs. No serious adverse drug reactions or new safety concerns were identified.Findings from this large, cross-sectional, observational, multicenter study indicate that first-generation AEDs sodium valproate and phenytoin continued to be used in a substantial number of patients on monotherapy and combination therapy in India, even though an increasing trend toward use of second-generation AEDs was noted in clinical practice.

Children suffering from epilepsy are maintained on antiepileptic drugs (AED) to ensure a reasonable quality of life. These drugs, however, are not without side effects. Notable among which is interference with the metabolism of folate with its attendant clinical implications such as megaloblastic anemia and bleeding diathesis.This study was carried out to determine the serum folate levels of children with epilepsy, compare the folate levels of these children with that of controls, the levels in subjects on different AED, and to investigate the possible effect of duration of AED use on serum folate levels.It was a comparative cross-sectional study involving children with epilepsy aged 2-14 years attending the paediatric neurology clinic of University of Ilorin Teaching Hospital (UITH), Ilorin. A total of 140 epileptic and 140 age-and-sex-matched nonepileptic children as controls were recruited into the study.Mean serum folate levels in subjects of 6.3 ± 1.6 ng/mL was significantly lower than 7.5 ± 1.5 ng/mL in controls (P = 0.001). The mean serum folate level in subjects on AED was comparable with the value in AED naïve subjects. The mean serum folate level was also comparable among subjects on carbamazepine, phenobarbitone, and valproate as monotherapy. There was no correlation between the duration of AED use and the mean serum folate levels (r = -0.180; P = 0.069).The mean serum folate level in subjects was significantly lower than the value in controls; but was comparable in subjects on carbamazepine, phenobarbitone, and valproate as monotherapy. There was no correlation between the duration of AED use and mean serum folate levels.

The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected population and the clinical characteristics. Currently, there are a lack of studies assessing the patient care pathways in ASD, particularly for comorbidity with epilepsy, despite its personal, familial, and economic impacts. Genetic abnormalities are likely implicated in the association of ASD and epilepsy, although they are currently detectable in only a small percentage of patients, and some known genetic and medical conditions are associated with ASD and epilepsy. There is no specificity of seizure type to be expected in children and adolescents with ASD compared with other neurodevelopmental disorders or epileptic syndromes. Treatment options include antiepileptic drugs (AED) and developmentally-based early interventions for ASD. Carbamazepine and lamotrigine are the most used AED, but further studies are needed to more precisely define the most suitable medications for this specific group of children with ASD.