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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
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[Molecular formula] C15H12N2O
[Molecular weight] 236.27
[Indications] This compound is widely utilized for epilepsy and neuralgia treat-
ment, and its application can be extended to diabetes insipidus, muscle tension disorders, schizophrenia, and emotional ailments. It effectively addresses diverse
forms of epilepsy, trigeminal and glossopharyngeal neuralgia, diabetes insipidus,
muscular tension, schizophrenia, and emotional disorders.
[Specications]
Tablets: 100mg and 200mg doses
Sustained-release tablets: 200mg dose
Capsules: 200mg dose
[Usage and dosage] For adults, the initial dosage ranges from 100 to 200mg once
or twice daily. The dose is gradually titrated to achieve optimal efcacy, typically
reaching 400mg/dose, taken two to three times daily, up to a maximum of 1600mg/
day for some patients. For children, 10–20mg/kg daily is administered based on
body weight. For patients less than 12months of age, the starting dose is 100–200mg
daily; for patients aged 1–5years, 200–400mg daily; for patients aged 6–10years,
400–600mg daily; and for patients aged 11–15years, 600–1000mg daily in divided
doses. For children aged 4 or younger, 20–60mg daily is the initial dose, increasing
by 20–60mg every other day. For those older than 4years, the initial dose may be
100mg daily, increasing by 100mg weekly.
[Adverse reactions] Adverse central nervous system reactions such as dizziness,
headache, ataxia, lethargy, fatigue, and double vision may occur. Additionally, gastrointestinal discomfort, such as nausea and vomiting, and skin allergic reactions are
possible side effects.
Clinical Application andBasic Research
The History ofCarbamazepine
The history of carbamazepine (CBZ) began in 1953 when it was discovered by
Swiss chemist Walter Schindler, leading to its commercial release in 1962. Its antiepileptic properties were rst described by M.Tchicaloff in 1963 [1]; J.D. Spillane
revealed its efcacy in treating trigeminal neuralgia in 1964 [2], while M.Donner
reported its benets in treating epilepsy and psychiatric symptoms in children and
adolescents in 1965 [3]. In 1967, V E Fernandez etal. discovered its pharmacological effects [4], and in 1968, T.H. Redpath etal. reported its side effects [5]. In 2022,
Roberto Santalucia et al. expanded its electroclinical phenotype for SLC13A5associated disorders, conrming the safety and efcacy of CBZ in nonstructural
early-onset epilepsy [6]. In 2024, Rashid HU etal. identied an association between
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ABCB1 gene polymorphisms and the clinical response to CBZ monotherapy in
epilepsy patients [7].
Antiepileptic Effect ofCarbamazepine
In a study of the antiepileptic effect of CBZ, P.Brittany etal. assessed the antiepileptic effects of CBZ in adults. The authors evaluated its pharmacology, pharmacokinetics, efcacy, safety, dosage, administration methods, potential drug interactions,
and therapeutic application. Intravenous CBZ administration serves as a temporary
alternative therapy for adult epilepsy patients. Pooling data from a phase 1 trial and
two open-label bioavailability studies comparing its effects via oral and intravenous
routes of administration, no signicant loss of seizure control was observed in
patients who switched to intravenous CBZ administration for short-term use. The
recommended intravenous dose is 70% of the oral dose and is infused for 30min
every 6h. Adverse effects were similar to those seen following oral administration,
except for increased infusion site reactions. Intravenous CBZ administration is a
viable option for adults who are unable to tolerate oral therapy for up to 7days after
oral stabilization, although its use is limited by unknown costs and unavailability in
the United States [8]. Additionally, Roberto etal. described a case of a child with a
recessive mutation in the SLC13A5 gene causing developmental and epileptic
encephalopathy. Early administration of CBZ signicantly improved clinical and
EEG features in this patient, expanding the understanding of SLC13A5-associated
disease and conrming the efcacy and safety of CBZ in treating nonstructural
early-onset epilepsy [7].
Studies ofCarbamazepine inSpecial Populations
Ivana Kacirova and colleagues conducted a cohort study to explore the transport of
CBZ and its active metabolite, 10,11-epoxide, in mature breast milk and breastfed
infants. They observed a highly signicant correlation between the levels of CBZ
and 10,11-epoxide in both maternal serum and breast milk. When enzyme-induced
ASMs were concurrently administered, there was a substantial increase of approximately 130% in the apparent maternal clearance of orally administered
CBZ.Combining CBZ treatment with valproic acid resulted in a signicant increase
in epoxide levels in both breast milk and maternal serum, but this had no impact on
breastfed infants. Their ndings indicated that the concentration of CBZ in breastfed infants did not reach the lower therapeutic threshold observed in the general
epilepsy population, and most epoxide concentrations remained below the lower
limit of quantication [9]. Wei Xu etal. conducted a retrospective study to evaluate
CBZ misuse, disease duration, and associated health issues among adolescents in
China. The median overdose threshold for CBZ was found to be 2000mg (range
from 800 to 5000mg). The majority of patients resided in urban and suburban areas
(76.47% and 52.94%, respectively) exhibited academic performance indicators in
the lowest third percentile (52.94%) and lacked parental supervision. Notably,
35.29% of the subjects reported signicant euphoria. Neurological symptoms were
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universal, with six (35.29%) patients experiencing coma (GCS < 8) and ve
(29.41%) enduring convulsions. Hemodialysis was administered to ve patients.
Although there was a trend toward a greater incidence of CBZ misuse in younger
individuals with repeated usage and lacking parental oversight compared to rsttime users (7/4 vs. 10/3428), this disparity was not statistically signicant. Repeat
users demonstrated a signicantly elevated toxic dose of 1035±1470mg, contrasting with the 646±0mg dose found in rst-time users (p=0.001). The euphoric
effects of CBZ may predispose adolescents to its misuse and subsequent overdose.
It is imperative to educate vulnerable youth about the dangers of CBZ abuse and
overdose to prevent future health complications [10]. Epilepsy, a chronic medical
condition, often accompanies adverse physical effects due to either the condition
itself or its prolonged treatment. Accurate prediction of oral drug pharmacokinetics
in children is crucial for optimizing pediatric drug efcacy and safety. Physiologically
based pharmacokinetic (PBPK) models play a key role in this endeavor. However,
gaps in our understanding of age-related physiological and anatomical changes hinder the application of these tools. This study aimed to explore age-related disparities
in the oral absorption of CBZ, a low-solubility compound, across children, infants,
and newborns. Philip etal. developed an oral absorption model using GastroPlus,
validated its extrapolation to younger age groups using clinical data, and conducted
sensitivity analyses on uncertain model parameters. Their ndings underscore the
signicance of age-specic physiological parameters, particularly clearance, in
achieving accurate simulation results. Sensitivity analysis revealed that CBZ
absorption was inuenced by factors such as solubility, particle size, small intestine
transit time, age group, and CBZ dosage. However, invitro dissolution experiments
employing the suggested pediatric biorelevant media exhibited no substantial agerelated variations in dissolution kinetics. An improved understanding of oral absorption in pediatric patients is imperative for enhancing exposure prediction accuracy
in children and bolstering condence in oral biopharmaceutical tools [11]. Yuka
Miyata-Nozaka etal. enrolled a cohort of 288 epilepsy patients from Malaysia, 63
of whom were prescribed CBZ monotherapy and 85 of whom received valproic acid
monotherapy. Notably, none of the patients exhibited drug allergy syndrome. Using
the Sequenom MassARRAY genotyping platform, the subject genotypes were
determined. This study revealed a signicant association between the CYP3A5
rs776746 polymorphism and the response to CBZ treatment (p=0.026), particularly within the Malay subgroup (p=0.006). Furthermore, a modest yet noteworthy
correlation was observed between the CYP3A5 rs776746 polymorphism and the
response to CBZ treatment among the Malaysian population. Similarly, the CYP3A5
rs776746 polymorphism exhibited an association with the valproic acid response
across all patients (p=0.037) and specically within the Malay population (p=0.05)
[12]. In a study, examining challenging-to-treat early-onset epilepsy linked to mutations in the sodium channel 2 subunit alpha (SCN2A), Tatjana Welzel and colleagues described an infant with SCN2A epilepsy who transitioned from phenytoin
to CBZ therapy to mitigate potential long-term neurotoxic effects. The transition
from high-dose phenytoin (20 mg/kg/day, concentration: ≥20 mg/L) to CBZ
(50–75 mg/kg/day, concentration: 9–12 mg/L) treatment during ketogenic diet
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therapy lasted 85 days, possibly due to signicant drug–drug and/or drug–food
interactions. Pharmacokinetic modeling analysis indicated that phenytoin-induced
CYP3A4 activity, while the CBZ concentration also inuenced self-induction,
resulting in an apparent clearance time increase of 2.5- to three-fold. Modeling suggested that lower CBZ concentrations were associated with reduced relative bioavailability (44%) during the ketogenic diet, potentially due to decreased absorption
(less favorable for this lipophilic drug), heightened intestinal/liver metabolism, and/
or reduced binding to ketogenic diet-associated proteins. These ndings underscore
the importance of monitoring CBZ concentrations during its introduction/removal
and highlight the necessity for high CBZ doses to achieve therapeutic levels, particularly in infants undergoing high-dose phenytoin treatment [13].
Side Effects ofCarbamazepine
The focus of an observational study led by Bianca Berghuis etal. was on investigating
the correlation between adverse reactions in individuals prescribed CBZ or oxcarbazepine and hyponatremia caused by these medications. Data on serum sodium levels and adverse effects were collected from 1370 epilepsy patients treated with CBZ
or oxcarbazepine (OXC) between 2017 and 2019. Hyponatremia was dened as
sodium levels ≤134mEq/L, with severe hyponatremia ≤128mEq/L.Among these
patients, 410 had a history of hyponatremia. Symptoms associated with CBZ and
OXC use were analyzed in 710 patients (410 with hyponatremia and 300 without),
yielding relevant information for 688 patients. This study revealed that 65% of patients
with hyponatremia experienced adverse reactions, while 21% of those with normal
sodium levels experienced adverse reactions (OR= 7.5, P≤ 0.001). Additionally,
83% of patients with severe hyponatremia and 55% with mild hyponatremia experienced adverse reactions (P≤0.001). Notably, signicant predictors of adverse reactions included the number of drugs (OXC vs. CBZ) and concurrent ASMs used.
Symptoms such as vertigo (28% vs. 6%), fatigue (22% vs. 7%), instability (19% vs.
3%), and diplopia (16% vs. 4%) were more prevalent in the hyponatremia group than
in patients with normal sodium levels. Researchers have concluded that patients with
hyponatremia face a sevenfold increased risk of adverse reactions during treatment,
emphasizing the importance of clinicians considering sodium levels when prescribing
CBZ and OXC [14
]. Chan- Wei Pan etal. described a case of CBZ-induced hypersensitivity syndrome in a 35-year-old patient with schizophrenia. Despite lacking previous food or drug allergies and testing negative for the HLA-B1502 genotype, the
patient developed high fever (39.4°C), leukopenia (1670/mm3), proteinuria, and bilateral pulmonary eld inltration after 19days of CBZ exposure. These adverse conditions were resolved upon discontinuation of CBZ treatment. This case underscores the
relevance of genetic predispositions beyond HLA-B1502in drug-induced hypersensitivity syndrome [15]. Sherifa etal. conducted a study to assess cochlear function in
patients with idiopathic epilepsy following treatment with CBZ.The subjects included
47 patients (mean age 34.56±7.11years, duration 17.84±7.21years) and 40 healthy
controls. Patients underwent pure tone audiometry and transient evoked otoacoustic
emission (TEOAE) analysis. One-third of the patients experienced hearing loss,
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predominantly mild bilateral loss. Compared to the control group, patients exhibited
reduced TEOAE amplitudes, particularly at higher frequencies (3 and 4kHz). The
TEOAE amplitudes showed signicant negative correlations with CBZ dosages
(3kHz: r=−0.554, p=0.008; 4kHz: r=−0.347, p=0.01), serum concentrations
(4kHz: r=−0.280, p=0.045), and treatment durations (3kHz: r=−0.392, p=0.008;
4kHz: r=−0.542, p=0.001). The study concluded that prolonged CBZ usage might
result in cochlear dysfunction and hearing impairment [16]. In their study, Caibing Xu
etal. identied a total of 1231 reports of Stevens-Johnson syndrome or toxic epidermal necrolysis associated with CBZ or oxcarbazepine. Among these, 1048 cases were
linked to CBZ use, comprising 668 cases of Stevens-Johnson syndrome and 380 cases
of toxic epidermal necrolysis. Additionally, 183 reports were associated with oxcarbazepine use, including 142 cases of Stevens-Johnson syndrome and 41 cases of toxic
epidermal necrolysis. The study revealed a greater risk of Stevens-Johnson syndrome
than of toxic epidermal necrolysis, with CBZ use posing a greater risk than that of
oxcarbazepine. These ndings support clinical observations and underscore the
importance of further clinical investigations into Stevens-Johnson syndrome and toxic
epidermal necrolysis linked to CBZ or oxcarbazepine use [17]. Wong CSM etal. identied the HLA-B15:11 genotype as a potential risk factor for severe cutaneous adverse
drug reactions in Chinese CBZ users negative for the HLA-B15:02 genotype. They
recommended additional screening for HLA-B15:11 genotype status in HLA-B15:02negative patients to mitigate the risk of adverse skin reactions [18]. Ohta K etal. presented a case involving an 11-year-old girl who experienced spontaneous and
stimulus-induced focal motor seizures following an overdose of CBZ.The patient had
been receiving CBZ (150mg daily) treatment for focal epilepsy since the age of 6. At
11, she inadvertently consumed 10 CBZ pills (totaling a dose of 1000mg) in lieu of
her normal morning dose, leading to a generalized seizure. Upon arrival at the hospital, she was in a comatose state. She presented with focal to bilateral tonic–clonic
seizures triggered by painful stimuli or occurring spontaneously, with focal epileptoid
discharge evident on EEG.Her blood CBZ concentration was 40.4μg/mL, conrming
CBZ overdose. Remarkably, the patient’s condition improved without specic intervention, and she was discharged without neurological complications. The study concluded that while generalized seizures from CBZ overdose often result in fatal
outcomes or necessitate intensive care, the presence of focal seizures induced by
stimuli may signify a favorable prognosis for CBZ overdose [19]. Baylis S etal. demonstrated that the combination of continuous venovenous hemoltration (CVVH) and
resin hemoperfusion therapy reduced CBZ levels by 50% within 3h, from 16mg/L to
8mg/L.This approach facilitated a signicantly faster CBZ clearance rate than CVVH
alone or without invitro drug elimination during the initial hours. The combined therapy effectively eliminated nearly 35mg/h CBZ.The study concluded that the combined approach of continuous renal replacement therapy and hemoperfusion is simple
to administer, considered safe, and synergistically enhances CBZ clearance by leveraging the efcacy of each modality [20]. Ran D etal. described a case involving a
70-year-old Chinese man who developed pruritic follicular papules and erythema on
the trunk and limbs, along with facial, lip, and ear edema and erythema, over a span
of 3days. Initially, the lesions presented as facial edema and erythema, followed by
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the formation of follicular papules on the body and limbs. The patient experienced no
other symptoms. The rash emerged 5days after initiating CBZ therapy at an oral dose
of 100mg twice daily for trigeminal neuralgia. CBZ treatment was promptly discontinued upon onset of rash. There was no recent history of infection, underlying conditions, or concurrent medication use. Rapid resolution of symptoms ensued following
CBZ cessation and administration of systemic corticosteroids. This case underscores
the importance of recognizing this rare CBZ-induced rash, known as follicular mucosal disease, and prompting clinicians to remain vigilant for its occurrence [21]. Sarah
Perrot etal. described a case of rapidly evolving cerebellar syndrome in a patient with
epilepsy after CBZ administration. Serial MRI scans revealed progressive T2/uidattenuated inversion recovery signal abnormalities in the posterior fossa, accompanied by enhancement. Routine cerebrospinal uid analysis was unremarkable. The
presence of JC virus DNA in the cerebrospinal uid conrmed progressive multifocal
leukoencephalopathy (PML). The sole immune abnormalities detected were hypogammaglobulinemia and chronic lymphocytopenia. Following discontinuation of
CBZ treatment, lymphocyte counts and immunoglobulin levels normalized, and the
PML resolved with clinical improvement. The patient did not receive PML-specic
treatment. The authors hypothesize that CBZ-induced mild immunosuppression sustained PML and that the discontinuation of CBZ restored immune function, leading to
PML resolution. ASMs-associated effects on immune function and infection risk may
exacerbate epilepsy-associated morbidity and mortality. Further investigations are
warranted to elucidate the prevalence of immune dysfunction and infections in patients
receiving treatment with ASMs such as CBZ and explore potential interventions to
mitigate infection risk [22]. Bao-Luen Chang etal. observed a decrease in CBZ prescriptions across epilepsy patients from 7% (2000–2003) to 6% (2004–2010) and
further to 4% (2011–2017). The screening rates increased from 0% for CBZ nonusers
and 0.5% for CBZ users in 2011 to 0.8% and 16%, respectively, in 2017. The mean
three-month incidence of severe cutaneous adverse reactions (SCARs) per 10,000
episodes signicantly decreased from stage 1 to stage 2in CBZ users (6.91 vs. 3.09,
p< 0.0001) and nonusers (1.96 vs. 1.65, p < 0.0001). The incidence of StevensJohnson syndrome/toxic epidermal necrolysis (SJS/TEN) signicantly decreased
from stage 1 to stage 2in CBZ users (2.94 vs. 1.93, p<0.001) but not in nonusers
(0.71 vs. 0.74, p=0.1492). In phase 2, the incidence of SCARs was signicantly
negatively correlated with screening rates in both CBZ users (r=−0.38, p=0.0342)
and nonusers (r=−0.180, p<0.001). However, no signicant correlation was found
between SJS/TEN incidence and screening rate. The study concluded that identifying
HLA-B*1502 alleles in patients with these conditions and avoiding CBZ treatment
are crucial for preventing CBZ-induced serious adverse events [23]. I Demir etal.
reported that the semi-circular canals (VOR) of gainslateral semi-circular canals
(SCCs) were 0.878±0.057 and 0.921±0.045in patients and healthy controls, respectively (p= 0.024). A reduced left-lateral SCCs VOR gain was detected in patients
(0.885±0.062 and 0.868±0.063) (p=0.011 and p=0.001). The lateral SSC VOR
gain (0.902±0.046) was lower in patients who used CBZ for >10years than in those
who used CBZ for <10years (0.843±0.055) (p=0.008). Conclusions: Lateral (right/
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left) SCCs VOR gain was relatively reduced in epilepsy patients treated with CBZ,
especially in those who had used CBZ long term (>10years) [24].
Basic Research onCarbamazepine
In their study aiming to understand the relationship between genetic variations in
drug receptor genes and the response to CBZ in epilepsy patients, Fan-Cheng Kong
etal. genotyped adult epilepsy patients (n=257) receiving CBZ monotherapy and
combination therapy and divided the patients into drug-sensitive and drug-resistant
groups according to the criteria of the International League Against Epilepsy. They
examined single nucleotide polymorphisms (SNPs) related to PXR, CAR and AHR
treatment, which mainly represent alleles associated with the risk of drug resistance.
Moreover, they created a reference sequence set for gene interaction analysis based
on SNPS.They did not observe signicant effects of PXR- or AHR-related gene
polymorphisms. However, the authors observed an interaction between the CAR
rs2502815 variant and the CBZ response. In patients receiving CBZ monotherapy
or combination therapy, the GG genotype of the CAR rs2502815 variant (homozygous with wild-type) was independently linked to the CBZ response after adjusting
for variables [OR= 0.389, 0.203–0.743, 0.389–0.303–0.743, 0.389–0.303–0.743,
0.389–0.2815, 0.389–0.203–0.743; p=0.004]. Case–control analysis of haplotype
and gene interactions for CBZ response yielded negative results. These ndings
offer clinical insights into genetic predispositions inuencing drug responses associated with CAR variants in epilepsy patients, highlighting a potential interaction
between the CAR rs2502815 polymorphism and CBZ response [25]. In a separate
investigation, Timothy A Simeone etal. utilized a multielectrode array to explore
the effects of CBZ treatment on hippocampal sharp wave ripples (SPW-Rs) and
multiple hippocampal synapses. They discovered that CBZ at treatment-relevant
concentrations (IC50=37μM) alters the core characteristics of ripples, which is
important for information processing and integration. Furthermore, CBZ inhibited
neurotransmission in a synapse-specic manner. CBZ’s inhibitory effect was most
pronounced at the medial perforant path to CA3 and at mossy bers to CA3 synapses (IC50=~30 and 60μM, respectively), and it was least effective in the medial
perforant path to the dentate granule cell synapse (IC50=~120 μM). They suggested that the synapse-specic inhibition of neurotransmission of CBZ diminishes
SPW-Rs, potentially contributing to the cognitive impairment observed at therapeutic doses of CBZ [26]. Ming-Liang Zhang et al. investigated the associations
between ABCB1, EPHX1 and SCN1A gene polymorphisms and CBZ metabolism
and drug resistance. The authors searched the PubMed, EMBASE, Cochrane
Library, CNKI, Chinese Science and Technology Journal, Chinese Biomedical CD
and Wanfang databases (up to April 2021) to include 18 studies encompassing 3293
epilepsy patients. They found that the ABCB1 c.3435C>T polymorphism correlated
signicantly with changes in the concentration–dose ratio of CBZ (CDR CBZ) (CC
vs. CT, OR=0.25 (0.08–0.42), P=0.004). The EPHX c.416A>G polymorphism
was observed to modify CBZ-10,11-trans-dihydrodiol (CDR CBZD) (AA vs. GG,
OR=0.48 (0.01–0.96), P=0.045; AG vs. GG, OR=0.68 (0.16–1.20), P=0.010)
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and the ratio of CDR CBZD to CBZ-10,11-epoxide (CBZE) (CDR CBZD: CDR
CBZE) (AG vs. GG, OR=0.83 (0.31–1.36), P=0.002). Additionally, the ABCB1
c.3435C>T polymorphism signicantly inuenced CBZ resistance (CC vs. TT,
OR=1.78 (1.17–2.72), P=0.008; CT vs. TT, OR=1.60 (1.12–2.30), P=0.01;
CC+CT vs. TT, OR=1.61 (1.15–2.26), P=0.006). These ndings suggest that
genetic variations in ABCB1 c.3435C>T and EPHX1 c.416A>G may regulate CBZ
metabolism and drug resistance in epilepsy patients [27]. Zhang Y etal. examined
the adsorption behavior of ubiquitous CBZ (CBZ) and four microplastic (MP) models, including original and aged forms of polyethylene, polyvinyl chloride, polyethylene terephthalate, and polystyrene. They investigated the adsorption isotherms,
kinetics, and desorption and analyzed MP changes during aging using various techniques, scanning electron microscopy, contact angle measurements, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. This study
revealed that aging increased the MP adsorption capacity for CBZ and extended the
desorption lag by altering the surface characteristics. By applying the extended
Derjaguin–Landau–Verwey–Overbeek (XDLVO) theory in an innovative manner,
they calculated the interfacial free energy, revealing a decrease in hydrophobic
interactions and a slight increase in van der Waals forces after aging. Overall, this
work elucidated the adsorption mechanism of CBZ on original and aged MPs and
provided insights into the adsorption of neutral organic compounds on MPs, providing valuable information for future research [28]. Kanoot Jaruthamsophon etal.
employed ow cytometry, proliferation analysis, ELISA, and ELISPOT assays to
characterize the phenotype, function, HLA allelic restriction, response pathway, and
cross-reactivity of CBZ-specic T-cells. They investigated the association between
HLA class II allelic restriction and CBZ hypersensitivity utilizing the allelic frequency network database. Through their study, they generated 44 CD4+ CBZspecic polyclonal T-cells and observed their restriction to HLA-DR, particularly
HLA-DRB107:01. This CD4+-mediated response was attributed to a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the
CD8+ response, CBZ-stimulated CD4+ clones were found to secrete granulysin, a
signicant mediator of Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN). Database analysis revealed an association between HLADRB107:01 and CBZ-induced SJS-TEN. These results imply that HLA class II
antigen presentation plays a role in CBZ hypersensitivity. Further investigations
into HLA class II molecules and drug-reactive CD4+ T-cells are warranted to
enhance our understanding of the pathogenesis of drug hypersensitivity [29].
Carbamazepine intheTreatment ofFocal Epilepsy
V A Karlov etal. utilized the epileptiform discharge index (EDI) to assess the efcacy and tolerability of CBZ sustained-release tablets in the treatment of adults with
new-onset focal epilepsy (FE). Their study included 62 males (61.3%) and 24
females (38.7%) with new-onset focal epilepsy aged 18–95 years (mean age
42.9±18.4years). Each patient underwent video EEG monitoring and EDI evaluation at every visit. They observed a signicant 4.3-fold reduction in total EDI from
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baseline to the end of the 12-month follow-up period (p<0.001). The seizure-free
rate was 0.3% (n=25), with an effective rate of 21.0% (n=13). They speculate that
CBZ demonstrates efcacy and promise as an initial monotherapy for FE [30].
Population Pharmacokinetics ofCarbamazepine
Vincent LM Yip etal. investigated the impact of clinical and genetic factors on the
pharmacokinetics (PK) of CBZ and its three metabolites, which are known to be
chemically reactive or formed through reactive intermediates. They collected a
combination of rich and sparse PK samples from healthy volunteers and epilepsy
patients and genotyped 20 single nucleotide polymorphisms across 11 genes known
to be involved in CBZ and CBZ 10, 11-epoxide metabolism or transport in all subjects. Their study included 248 observations from 80 subjects. The total maternal
CBZ clearance was determined to be 1.96L/h, with a central volume of distribution
of 164L and an absorption rate constant of 0.45h−1. The coadministration of the
total daily dose and of phenytoin was identied as a signicant covariate affecting
total CBZ clearance. Furthermore, the EPHX1–416 G/G genotype was highlighted
as an important covariate for CBZ 10,11-epoxide clearance. The authors concluded
that CBZ clearance was inuenced by the combined administration of total dose and
phenytoin sodium, while CBZ 10,11-epoxide clearance was affected by genetic
variants in the microsomal epoxide hydrolase gene [31].
Kacirova I etal. investigated CBZ concentrations in various biological samples,
including maternal serum, colostrum, and neonatal serum. They found a range of
concentrations in maternal serum (1.0–11.2mg/L for CBZ and 0.3–4.4mg/L for
epoxide), colostrum (0.5–6.8mg/L for CBZ and 0.3–2.4mg/L for epoxide), and
neonatal serum (0.5–4.7mg/L for CBZ and 0.3–1.7mg/L for epoxide). The median
milk/maternal serum concentration ratio of CBZ was 0.45 (epoxide 0.71), the
median neonatal/maternal serum concentration ratio of CBZ was 0.20 (epoxide
0.41), and the median neonatal serum/milk concentration ratio of CBZ was 0.38
(epoxide 0.50). They observed a signicant correlation between CBZ concentrations in milk and maternal serum, as well as between milk and neonatal serum
concentrations. However, they noted that only one CBZ index in the serum of
breastfed neonates fell within the reference range for the general epilepsy population, with more than half below the lower limit of quantication. Consequently, the
authors concluded that routine monitoring of serum CBZ concentrations in breastfed newborns may not be necessary. Nonetheless, they recommended close observation of newborns for potential adverse effects, with serum concentration
measurements warranted if such effects are observed [32]. Yuito Fujita etal. conducted PPK analysis and showed that the couse of CBZ increased the clearance of
PER.They found that their PPK models provided a good description of the observed
data with low bias, as indicated by the t quality chart. The mean error, mean absolute error and root-mean-square error values derived from the semimechanical
model were smaller than the PER concentrations predicted by the empirical PPK
model for CBZ patients. Conclusions: The authors developed two different
approaches to PPK models based on electronic medical records data to characterize
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the pharmacokinetics of PER.They emphasized that their PPK model supports the
clinical use of PER, suggesting its efcacy and utility in practice [33].
Additional Studies ofCarbamazepine
Amara Gul etal. conducted a case–control study to examine the effects of CBZ on
emotional intelligence and mindfulness among patients with epilepsy. They
recruited 80 subjects, including 40 epilepsy patients (50%) with an average age of
37.92 ± 9.09 years and 40 control patients (50%) with an average age of
37.80±9.00years. Emotional intelligence and mindfulness indices were signicantly lower in patients with epilepsy than in controls (p<0.001). Patients demonstrated improved emotional intelligence and mindfulness indices following CBZ
treatment compared to their baseline scores (p<0.05). Thus, the authors suggest
that CBZ may be effective in enhancing emotional intelligence and mindfulness
indices among individuals with epilepsy [34].
Jason etal. investigated the potential of the sodium channel blocker CBZ to protect beta cells from inammatory cytokines in vitro. The authors supplemented
LabDiet 5053 female nonobese diabetic (NOD) mice with 0.5% w/w CBZ to assess
its effects, resulting in a serum CBZ level of 14.98±3.19μM.Notably, CBZ-treated
animals exhibited an approximately 50% reduction in diabetes incidence at 25weeks,
as indicated by fasting blood glucose levels. Additionally, improved glucose tolerance was observed in CBZ-fed NOD mice at 6weeks of age, preceding the onset of
diabetes in the population. Although fewer islets were detected in CBZ- treated NOD
mice at 6weeks of age, no differences were detected in CD4 and CD8 T-cell composition or circulating inammatory markers in pancreatic lymph nodes. These ndings
suggest that CBZ reduces the occurrence of type 1 diabetes in NOD mice by preserving functional beta cell volume. However, due to the growing concern of drug abuse,
it has been found that CBZ is discharged into aquatic environments via urban sewage, posing potential harm to aquatic organisms [35]. Bai Zhonghui et al. used
zebrash, an aquatic vertebrate, as a model to comprehensively evaluate the hepatotoxicity of CBZ.Larvae were infected at 72–144hours postfertilization (hpf) with
0.07, 0.13, or 0.26mmol/L CBZ and 0.025, 0.05, or 0.1mmol/L CBZ for 28days.
There were signicant changes in liver histopathology and size, indicating that CBZ
had severe hepatotoxic effects on larvae and adults. Oil Red O staining revealed substantial lipid deposition in the liver of both larvae and adults exposed to
CBZ. Moreover, CBZ exposure promoted hepatocyte apoptosis, as evidenced by
TUNEL staining, which was attributed to increased ROS content. The subsequent
downregulation of gene expression related to the Wnt pathway in each infected group
suggested that CBZ may inhibit liver development through the Wnt/β-catenin signaling pathway. These ndings highlight the hepatotoxicity of CBZ in zebrash and
elucidate its mechanism of action, providing valuable insights into environmental
issues associated with CBZ exposure [36]. Giulia etal. conducted a retrospective
observational study to assess the effectiveness and tolerability of CBZ and oxcarbazepine in a large cohort of patients diagnosed with classic (254 patients), secondary (60 patients), and idiopathic (40 patients) trigeminal neuralgia. Propensity score