Degradation of carbamazepine by the UVA-LED365/ClO2/NaClO process: Kinetics, mechanisms and DBPs yield.

A mixed oxidant of chlorine dioxide (ClO2) and NaClO was often used in water treatment. A novel UVA-LED (365 nm)-activated mixed ClO2/NaClO process was proposed for the degradation of micropollutants in this study. Carbamazepine (CBZ) was selected as the target pollutant. Compared with the UVA365/ClO2 process, the UVA365/ClO2/NaClO process can improve the degradation of CBZ, with the rate constant increasing from 2.11×10-4 sec-1 to 2.74×10-4 sec-1. In addition, the consumption of oxidants in the UVA365/ClO2/NaClO process (73.67%) can also be lower than that of UVA365/NaClO (86.42%). When the NaClO ratio increased, both the degradation efficiency of CBZ and the consumption of oxidants can increase in the UVA365/ClO2/NaClO process. The solution pH can affect the contribution of NaClO in the total oxidant ratio. When the pH range of 6.0-8.0, the combination process can generate more active species to promote the degradation of CBZ. The change of active species with oxidant molar ratio was investigated in the UVA365/ClO2/NaClO process. When ClO2 acted as the main oxidant, HO• and Cl• were the main active species, while when NaClO was the main oxidant, ClO• played a role in the system. Both chloride ion (Cl-), bicarbonate ion (HCO3-), and nitrate ion (NO3-) can promote the reaction system. As the concentration of NaClO in the reaction solution increased, the generation of chlorates will decrease. The UVA365/ClO2/NaClO process can effectively control the formation of volatile disinfection by-products (DBPs), and with the increase of ClO2 dosage, the formation of DBPs can also decrease.

Meta-analysis and sequential analysis of acupuncture compared to carbamazepine in the treatment of trigeminal neuralgia.

BACKGROUND: In this randomized controlled trial (RCT) comparing current acupuncture with carbamazepine for trigeminal neuralgia, meta- and sequential analyses were utilized. AIM: To guide clinical decision making regarding the treatment of trigeminal neuralgia with carbamazepine. METHODS: The RCT literature on needle comparison was searched in various Chinese biomedical databases including Chinese Biomedical Literature Database, Wanfang Data, VIP Database, as well as international databases such as Excerpt Medica Database, Cochrane Library, PubMed, and Web of Science, along with related clinical registration platforms such as World Health Organization International Clinical Trial Registry Platform, ChiCTR, and Clinical Trials up to 1 April 2020. Risk of bias was evaluated using the Cochrane Collaborative Risk Bias tool, primary outcome measures (pain reduction) were analyzed using STATA meta-analysis, outcome measures were analyzed using trial sequential analysis 0.9.5.10 Beta sequential analysis, GRADE was used to assess the evidence, and adverse reactions were documented. RESULTS: This study analyzed 16 RCTs with a total of 1231 participants. The meta-analysis revealed a statistically significant difference in pain reduction between acupuncture and carbamazepine [standardized mean difference (SMD) = 1.47; 95% confidence interval (CI): 0.99-1.95], although the quality of evidence was deemed to be of extremely low quality. Cumulative meta-analysis based on the year of publication indicated that carbamazepine treatment first demonstrated a statistically significant difference in pain reduction in 2014 and remained relatively stable over time [SMD = 1.84; 95%CI: 0.22-3.47]. Additionally, the number of adverse events associated with acupuncture was significantly lower compared to carbamazepine. CONCLUSION: Acupuncture for trigeminal neuralgia is better than analgesia and safer than carbamazepine; however, firm conclusions still require a high-quality, multicenter, large-sample RCT to confirm these findings.

Multiple sclerosis relapse presenting as trigeminal neuralgia.

I present here a case of trigeminal neuralgia (TGN), which is a highly disabling disorder characterized by brief and recurrent shock-like episodes of facial pain. TGN occurs in 2% of people with MS. A 54-year-old woman diagnosed with multiple sclerosis (MS) in 2008 and who was in remission stopped taking her disease-modifying therapy (DMT) in 2018 due to a lack of relapses presented to our facility with excruciating right facial pain. Magnetic resonance imaging (MRI) of the brain with gadolinium showed enhancing plaque involving the proximal cisternal portion of the right trigeminal nerve on axial and sagittal sections. She was started on carbamazepine 300 mg 4 times a day. This case highlights the need for early diagnosis by MRI with gadolinium enhancement and prompt initiation of treatment helped her pain to subside and was able to return a week later to the MS clinic to be restarted on her prior DMT to prevent further MS relapses.

Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds.

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

Electrical Status Epilepticus during Sleep in a Male Filipino with Rare Nonsense Mutation Variant of Sotos Syndrome on Carbamazepine Monotherapy.

Electrical status epilepticus during sleep (ESES) is an electrographic pattern associated with specific genetic disorders, brain malformations, and use of some antiseizure medications. This case report aims to present the management of ESES in Sotos syndrome (SoS) on carbamazepine. A nine-year-old Filipino male with clinical features suggestive of overgrowth syndrome presented with febrile seizure at one year old. Cranial imaging showed cavum septum pellucidum, corpus callosal dysgenesis, and ventriculomegaly. He was on carbamazepine monotherapy starting at three years old. A near continuous diffuse spike-wave discharges in slow wave sleep was recorded at nine years old hence shifted to valproic acid. Follow-up study showed focal epileptiform discharges during sleep with disappearance of ESES. Next generation sequencing tested positive for rare nonsense mutation of nuclear receptor binding set-domain protein 1 confirming the diagnosis of SoS. Advanced molecular genetics contributed to determination of ESES etiologies. To date, this is the first documented case of SoS developing ESES. Whether an inherent genetic predisposition or drug-induced, we recommend the avoidance of carbamazepine and use of valproic acid as first-line therapy.

Nitrogen-doped mesoporous activated carbon from Lentinus edodes residue: an optimized adsorbent for pharmaceuticals in aqueous solutions.

In this study, phosphoric acid activation was employed to synthesize nitrogen-doped mesoporous activated carbon (designated as MR1) from Lentinus edodes (shiitake mushroom) residue, while aiming to efficiently remove acetaminophen (APAP), carbamazepine (CBZ), and metronidazole (MNZ) from aqueous solutions. We characterized the physicochemical properties of the produced adsorbents using scanning electron microscopy (SEM), nitrogen adsorption isotherms, and X-ray photoelectron spectroscopy (XPS). MR1, MR2, and MR3 were prepared using phosphoric acid impregnation ratios of 1, 2, and 3 mL/g, respectively. Notably, MR1 exhibited a significant mesoporous structure with a volume of 0.825 cm3/g and a quaternary nitrogen content of 2.6%. This endowed MR1 with a high adsorption capacity for APAP, CBZ, and MNZ, positioning it as a promising candidate for water purification applications. The adsorption behavior of the contaminants followed the Freundlich isotherm model, suggesting a multilayer adsorption process. Notably, MR1 showed excellent durability and recyclability, maintaining 95% of its initial adsorption efficiency after five regeneration cycles and indicating its potential for sustainable use in water treatment processes.

Effects of species of origin and mode of induction of microsomes on carbamazepine-induced cell toxicity.

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs.

Case report: Gait-induced palilalia in a patient with hemiplegia due to cerebral infarction.

Background: Palilalia is a type of speech characterized by compulsive repetition of words, phrases, or syllables. Several reports have noted that palilalia can occur in response to external verbal stimuli. Here, we report, for the first time, a patient with palilalia induced by gait, which we call "movement-related palilalia." Case presentation: Eleven months after the onset of cerebral infarction sparing the right precentral gyrus and its adjacent subcortical regions, a 63-year-old, left-handed Japanese man was referred for psychiatric consultation because of a complaint of irritability caused by the stress of compulsive repetition of a single meaningless word, "wai." The repetition of a word, palilalia, in this case, was characterized by its predominant occurrence during walking and by its melodic tones. The palilalia during walking disappeared almost completely after 5 months of treatment with carbamazepine 600 mg. Conclusion: Palilalia induced by gait can occur in patients with a history of cerebral infarction. This palilalia during walking may be due to the reorganization of networks in areas nearby or surrounding cerebral infarcts.

Three siblings with self-limited familial infantile epilepsy with PRRT2 mutation: A case series.

We report three sisters with self-limited familial infantile epilepsy, caused by a mutation in proline-rich transmembrane protein2. Self-limited familial infantile epilepsy has been established as a distinct epileptic syndrome characterized by focal seizures in clusters of infantile-onset. The seizure types of our cases were focal with or without secondary generalization. The seizures manifested at 3-5 months of age, and each lasted 1-2 min. All three sisters fulfilled the criteria for self-limited familial infantile epilepsy, except in one case who showed interictal spikes in the right central area. The seizures were controlled with carbamazepine. When carbamazepine treatment was started, one case developed a rash, and her treatment was switched to valproic acid. However, the seizures persisted in this case such that carbamazepine was restarted. The rash did not recur. Electroencephalography showed spikes in only one case on interictal electroencephalography. All three sisters were developmentally normal, and no dyskinesia was observed during follow-up. All three sisters and their father, but not their mother, had the following pathogenic variant in proline-rich transmembrane protein2: NM_001256442.2(PRRT2): c.649dup[p.(Arg217Profs*8)]. This mutation has been identified in the majority of families with self-limited familial infantile epilepsy, paroxysmal kinesigenic dyskinesia, and/or infantile convulsion and choreoathetosis. Their father had no history of either self-limited familial infantile epilepsy or paroxysmal kinesigenic dyskinesia. The lack of a clear genotype-phenotype correlation was demonstrated in our cases with this proline-rich transmembrane protein2 mutation.

Bioconcentration of pharmaceuticals by aquatic flora in an Australian river system.

Pharmaceuticals are emerging contaminants in the environment and are a ubiquitous presence in rivers downstream of wastewater treatment plant outfalls. Questions remain about the persistence of pharmaceuticals in rivers, and the uptake and bioconcentration of pharmaceuticals by aquatic plants. Our study took place in the Yarrowee/Leigh/Barwon River system in southeastern Australia. We quantified the concentrations of five pharmaceuticals (carbamazepine, primidone, propranolol, tramadol, and venlafaxine) in surface water at five sites along a 144-km stretch of river, downstream of the presumed primary point source (a wastewater treatment plant outfall). We quantified pharmaceuticals in the leaves of two aquatic plant species (Phragmites australis and Vallisneria australis) sampled at each site, and calculated bioconcentration factors. All five pharmaceuticals were detected in surface waters, and the highest detected concentration exceeded 500 ng.L-1 (tramadol). Four of the pharmaceuticals (all except tramadol) were detected and quantified at all sites, including the furthest site from the outfall (144 km). Carbamazepine showed less attenuation with distance from the outfall than the other pharmaceuticals. Carbamazepine and venlafaxine were quantified in the leaves of both aquatic plant species (range: 10-31 ng.g-1), and there was evidence that bioconcentration factors increased with decreasing surface water concentrations. The study demonstrates the potential long-distance persistence of pharmaceuticals in river systems, and the bioconcentration of pharmaceuticals by aquatic plants in natural ecosystems. These phenomena deserve greater attention as aquatic plants are a potential point of transfer of pharmaceuticals from aquatic ecosystems to terrestrial food webs.

Pharmacokinetic profile of phenytoin in dried blood spot with high-performance liquid chromatography-photodiode array.

Phenytoin is a first-line antiepileptic drug with narrow therapeutic range and follows non-linear pharmacokinetics. Pharmacokinetics of phenytoin have been studied in plasma matrix before, however, there were several disadvantages. This study aimed to obtain partial validation data of the analytical method and the pharmacokinetic profile of phenytoin in Dried Blood Spot (DBS) of six healthy subjects. DBS has the advantage of only requiring small sample volumes and could be transported more efficiently. Phenytoin along with carbamazepine as the chosen internal standard was analyzed with a reversed-phase high performance-liquid chromatography system and a photodiode array detector at 205 nm. The results of partial validation, which evaluated the linearity, within-run accuracy, and precision, were within the criteria acceptance range. The pharmacokinetic profile showed that average AUC0-t was 83.81 ± 37.32 µg.h/mL and AUC0-∞ was 83.65 ± 38.89 µg.h/mL with an average ratio of 93%. Previous study quantifying phenytoin in the plasma matrix found the average AUC0-t was 39.41 ± 8.57 µg.h/mL and AUC0-∞ was 42.94 ± 9.55 µg.h/mL. Despite the difference between parameters of phenytoin analyzed in DBS and plasma matrices, the pharmacokinetic profiles obtained from both matrices were similar indicated by comparable concentration-time curves, thus, proving that DBS matrix can be used interchangeably with the plasma matrix as a more comfortable and effective alternative to phenytoin quantification in blood.

Clinical and electroencephalographic correlates of carbamazepine-associated hiccups in epileptic patients.

Carbamazepine, a commonly prescribed antiepileptic drug, is known to induce hiccups in a subset of epileptic patients. Although relatively uncommon, can have significant clinical implications. This comprehensive review delves into the clinical and electroencephalographic correlates of carbamazepine-associated hiccups, aiming to enhance understanding and management of this neurological side effect. The authors' review synthesizes qualitative epidemiological data, revealing that carbamazepine-induced hiccups occur in a subset of patients receiving the medication, with reported incidence rates ranging from 2.5 to 40%. Despite its relatively low prevalence, hiccups pose substantial challenges for patients and healthcare providers. Complications associated with carbamazepine-induced hiccups include disruption of sleep, impaired social functioning, and decreased quality of life, underscoring the clinical significance of this side effect. Effective management strategies can be implemented through a multidisciplinary approach, including collaboration among neurologists, pharmacists, and other healthcare professionals. These may include dose adjustments, medication discontinuation, and adjunctive therapies such as diaphragmatic breathing exercises or acupuncture. Additionally, close monitoring for adverse effects and timely intervention are essential to mitigate the impact of hiccups on patient well-being. Essentially, carbamazepine-induced hiccups represent a clinically relevant phenomenon that warrants attention in the management of epilepsy. By recognizing the clinical manifestations, understanding the underlying pathophysiology, and implementing evidence-based management strategies, healthcare providers can optimize patient care and improve outcomes in this patient population.

Embryo-Fetal Developmental Toxicity of Carbamazepine Administered Orally in Wistar Rat.

Carbamazepine is an anticonvulsant medication commonly used to treat epilepsy and other neurological disorders. The purpose of this study was to assess the impact of carbamazepine on prenatal development, including maternal-fetal, external, visceral, and skeletal toxicity. Additionally, the study aimed to investigate the effects of orally administered Carbamazepine at a lower dose range in Wistar rats. Pregnant female rats were randomly distributed into control (G1) group administered with distilled water orally (n=8), low dose (G2) group administered at 25mg/kg, intermediate dose (G3) group at 50mg/kg, and high dose (G4) group at 100mg/kg through oral gavage from gestation day (GD) 5-19. Pregnant female rats were scheduled to necropsy on gestation day (GD) 20. During the evaluation, the uterus was observed for number of live or viable fetuses, dead fetuses, early resorptions, late resorptions, number of corpora lutea and the sex ratio (m/f) per litter. Further, fetuses were subjected to materno-fetal examination which included observation for placenta, amniotic fluid, and umbilical cord followed by external evaluation. Additionally, half of the fetuses were subjected to visceral, craniofacial evaluation and other half of the fetuses were subjected to skeletal evaluation by double staining method using Alcian Blue for cartilages and Alizarin Red S for bones. It was observed that there was a significant decrease in the rate of pregnancy in the intermediate dose (G3) group and in high dose (G4) group when compared with the control group. Moreover, treatment with the Carbamazepine caused significant increase in fetal malformations such as dilation of lateral and third ventricle in brain, in intermediate dose (G3) group and high dose (G4) group when compared with the control (G1) group, dilation of ureters in high dose (G4) group. Fetal skeletal malformations like bent and nodulated ribs were also observed in intermediate dose (G3) group. Existing research substantially supports the claim that carbamazepine can cause teratogenic effects and prenatal development toxicity even at a lower dose range.

Population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults.

BACKGROUND: Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults. RESEARCH DESIGN AND METHODS: Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations. RESULTS: Our results indicated that the adult patients' ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation. CONCLUSIONS: Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

Thiamylal serum concentration for refractory convulsive status epilepticus while associated decreased concentrations of concomitant antiepileptics: a case report.

BACKGROUND: Treating refractory status epilepticus (RSE) remains a challenge. Thiamylal can be used as a second- or third-line treatment; however, its potential to induce cytochrome P450 (CYP) activity may reduce the concentration of antiepileptic drugs (AEDs) administered prior to thiamylal. This report details a case of RSE patient treated with thiamylal, with monitored concentrations of thiamylal and other AEDs. CASE PRESENTATION: A 72-year-old healthy man developed RSE. Despite the administration of various AEDs, his seizures were not resolved. Thiamylal was then administered at an initial bolus dose of 2.1 mg/kg, followed by a continuous infusion of 4.2-5.2 mg/kg/h. The initial thiamylal concentration was observed at 7.8 µg/mL, increasing to 35.2 µg/mL before decreasing after dose reduction and cessation. Concurrently, the concentration of concomitant carbamazepine decreased from 5.59 µg/mL to 2.1 µg/mL and recovered as thiamylal concentration decreased. Lesser impacts were noted for other AEDs. CONCLUSIONS: This case report underscored the efficacy of thiamylal in treating RSE. However, it also highlighted the need for clinicians to closely monitor the concentrations of concurrent AEDs, especially carbamazepine, during thiamylal therapy.

Arbidol, an antiviral drug, identified as a sodium channel blocker with anticonvulsant activity.

BACKGROUND AND PURPOSE: Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models. EXPERIMENTAL APPROACH: Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice. KEY RESULTS: Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model. CONCLUSIONS AND IMPLICATIONS: Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.

Pharmacogenetics of Carbamazepine: A Systematic Review on CYP3A4 and CYP3A5 Polymorphisms.

BACKGROUND AND OBJECTIVE: The association between carbamazepine (CBZ) metabolism and resistance in epilepsy and the genetic polymorphisms of CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) has been the subject of previous investigations with controversial results. We conducted a systematic review to assess the potential link between these polymorphisms and CBZ metabolism and resistance. METHODS: Identifying relevant studies, was carried out bay searching PubMed, Scopus, PharmGKB, EPIGAD, and PHARMAADME databases up until June 2023. The studies included in our analysis investigated the connection between CYP3A5 (rs776746 and rs15524) and CYP3A4 (rs2242480, rs2740574, rs35599367, rs12721627, and rs28371759) polymorphisms and CBZ metabolism and resistance. RESULTS: This review included a total of 23 studies and more than 2177 epilepsy patients. As a result the CYP3A4 (rs12721627 and rs28371759) polymorphisms are associated with reduced catalytic activity, where the CYP3A4 (rs2740574) polymorphism is linked to lower levels of CBZ-diol and decreased activity. It's been found also that the CYP3A5 (rs776746) polymorphism influences the dose-adjusted plasma levels of CBZ. CONCLUSION: Although these findings highlight the impact of genetic variations in the CYP3A4 and CYP3A5 genes on CBZ pharmacokinetics and pharmacodynamics, further studies across diverse populations are essential to enhance personalized epilepsy therapy in clinical settings.