Carbamazepine Blood Levels Research Articles

Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs. Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100-400mg/day (65 measures). Results: we enrolled 54 patients with a median age of 27.9years. The mean follow-up was 10.7months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(μg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(μg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = -0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6months evaluation of 4.53 (p = 0.03). Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as "victim" and as "perpetrator" of drug-drug interactions.

難治性徐脈より心肺停止を呈し体外循環導入にて救命し得たカルバマゼピン中毒の1例(A case of carbamazepine intoxication with cardiopulmonary arrest caused by intractable bradycardia that was treated with extracorporeal circulation)

要旨カルバマゼピンは抗てんかん薬で，中毒症状としてめまいや意識障害，不整脈が認められることが多い。カルバマゼピン過量服薬から徐脈性不整脈，心肺停止に至り体外循環を導入し救命した症例を経験した。症例は54歳の女性，既往に統合失調症がある。搬送当日，朝から希死念慮のためカルバマゼピンを過量服薬し，自宅で倒れているところを発見した家族が救急要請した。病院到着後に徐脈から心停止に移行した。心拍再開したが薬剤抵抗性の徐脈を認めたためVA–ECMOを導入した。入院4日目にVA–ECMOを離脱，10日目に人工呼吸器を離脱し35日目に退院となった。カルバマゼピンはナトリウムチャネルブロックの作用を有しており，催不整脈作用を有する。過量服薬時の徐脈性不整脈は治療抵抗性のため，循環不全もしくは心停止に至る症例ではVA–ECMOの導入が効果的であることが示唆された。

Measuring the appropriateness of carbamazepine and valproic acid prescribing and utilization using a newly implemented online system in the Tabuk Region of Saudi Arabia

Epilepsy is a common neurologic disorder, which is efficiently treated with carbamazepine and valproic acid. Moreover, Saudi Ministry of Health implemented a new E-system for Poison Control Centers called Awtar to enhance technology utilization in ensuring patients’ satisfaction and to improve treatment outcomes. Therefore, we conducted this study to assess appropriateness of indication of requests and therapeutic levels of carbamazepine and valproic acid in Tabuk area, North West Saudi Arabia. This is a retrospective observational study conducted in Poison Control & Forensic Chemistry Center, Tabuk, Saudi Arabia. Patients’ data were obtained for years 2018 and 2019. The blood levels of carbamazepine and valproic acid were measured by Therapeutic Drug Monitoring (TDM) Unit. We selected patients treated with either valproic acid or carbamazepine alone without any history of drug allergy. Data of 264 patients were extracted from Awtar E-system. Serum carbamazepine levels were within therapeutic range in 114 patients (75.50%), above-therapeutic range in 13 patients (8.61%) and sub-therapeutic levels in 24 patients (15.89%). Regarding serum valproic acid, it is within therapeutic range in 62 patients (54.87%), above-therapeutic range in 11 patients (9.73%) and sub-therapeutic levels in 40 patients (35.40%). In conclusion, this study gives information about partial appropriateness of usage of carbamazepine and low level of appropriateness of valproic acid. However, more efforts are needed to improve results of appropriateness of indication of antiepileptic drugs.

Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource limited setting: a comparative cohort study

BackgroundManagement of epilepsy during pregnancy in a resource-limited setting (RLS) is challenging. This study aimed to assess obstetric outcomes and effects on babies of women with epilepsy (WWE) exposed to Anti-epileptic drugs (AEDs) compared to non-exposed controls in a RLS.MethodsPregnant WWE were recruited from antenatal and neurology clinics of a tertiary care hospitals in Sri Lanka. Patients were reviewed in each trimester and post-partum. Medication adherence, adverse effects, seizure control and carbamazepine blood levels were monitored. Post-partum, measurements for anthropometric and dysmorphic features of the babies and congenital abnormalities were recorded. Age and sex matched babies not exposed to AED recruited as controls were also examined.ResultsNinety-six pregnant WWE were recruited (mean period of gestation 22.9 weeks). Mean age was 28 years and 48(50%) were primigravidae. Fifty percent (48) were on monotherapy, while 23.8, 15.9 and 4.1% were on two, three and four AEDs respectively. AEDs in first trimester (TM1) were carbamazepine (71%), valproate (25.8%) clobazam (29.5%), lamotrigine (7%) topiramate (5%) and others (3.4%). Sodium valproate use reduced significantly from T1 to T2(p < 0.05). Sub-therapeutic carbamazepine levels correlated positively (r = 0.547) with poor medication adherence (p = 0.009) and negatively (r = 0.306) with adverse effects (p = 0.002). Seventy-six WWE completed follow-up reporting w 75 (98.6%) live births and one T1 miscarriage (1.3%). Three (4.3%) were preterm. Majority (73.33%) were normal vaginal deliveries. Cesarean sections were not increased in WWE. Fifty-nine (61.45%) babies were examined. For those examined during infancy, 53 age and sex matched controls were recruited and examined.. Congenital abnormalities occurred in 5 (9.43%) babies of WWE [atrio-ventricular septal defect (2), renal hypoplasia (1), cryptorchidism (1), microcephaly (1)] compared to 2 (3.77%) in controls (2 microcephaly; p = 0.24). Fetal exposure to AEDs increased a risk of low birth weight (RR 2.8; p = 0.049). Anthropometric parameters of AED exposed babies were lower at birth but not statistically significant between the two groups (weight p = 0.263, length p = 0.363, occipito-frontal circumference (OFC) p = 0.307). However, weight (p = 0.009), length (p = 0.016) and OFC (p = 0.002) were significantly lower compared to controls at an average of 3.52 months.ConclusionMost pregnancies are unplanned in the RLS studied, and AEDs were altered during pregnancy. Congenital anomalies occurred at rates comparable to previous reports. Fetal exposure to AED had growth retardation in infancy compared to non-exposed babies.

Antiepileptic carbamazepine drug treatment induces alteration of membrane in red blood cells: Possible positive effects on metabolism and oxidative stress

Carbamazepine (CBZ) is an iminostilbene derivative commonly used for treatment of neuralgic pain and bipolar affective disorders. CBZ blood levels of treated patients are within the range of micromolar concentrations and therefore, significant interactions of this drug with erythrocytes are very likely. Moreover, the lipid domains of the cell membrane are believed to be one of the sites where iminostilbene derivatives exert their effects. The present study aimed to deeply characterize CBZ effects on erythrocytes, in order to identify extra and/or cytosolic cell targets. Our results indicate that erythrocyte morphological changes promoted by the drug, may be triggered by an alteration in band 3 functionality i.e. at the level of anionic flux. In addition, from a metabolic point of view this perturbation could be considered, at least in part, as a beneficial event because it could favour the CO2 elimination. Since lipid peroxidation, superoxide and free radical scavenging activities, caspase 3 activity and hemoglobin (Hb) functionality were not modified within the CBZ treated red blood cell (RBC), band 3 protein (B3) may well be a specific membrane target for CBZ and responsible for CBZ-induced toxic effects in erythrocytes. However some beneficial effects of this drug have been evidenced; among them an increased release of ATP and nitric oxide (NO) derived metabolites from erythrocytes to lumen, leading to an increased NO pool in the vasculature. In conclusion, these results indicate that CBZ, though considered responsible for toxic effects on erythrocytes, can also exhibit effects that at least in some conditions may be seen as beneficial.

Biochemical evidence for osteomalacia with carbamazepine therapy.

Many anticonvulsants are known to cause osteomalacia, however, carbamazepine has not previously been studied in this regard. We studied 31 patients on carbamazepine (mean dose 758 mg +/- s.d. 468 mg per day), as a single drug for epilepsy for a duration of 20.5 +/- 10 months. Three patients (10%) had hypocalcaemia, and serum calcium was significantly lower (P less than 0.01), and serum alkaline phosphatase significantly higher (P less than 0.05) than matched control subjects. Serum phosphorus was significantly inversely correlated and serum alkaline phosphatase was positively correlated with both dose and duration, but not blood levels of carbamazepine. These findings are consistent with mild biochemical changes of osteomalacia. None of the patients were symptomatic. Serum bilirubin (mean 2.6 +/- 1.4 mumol/l) was very significantly lower (P less than 0.01) than in controls. Both the calcium and bilirubin disturbances are probably due to carbamazepine causing hepatic microsomal enzyme induction.

Predictors of Response to Carbamazepine Extended-Release Capsules Treatment in Bipolar Disorder

Predictors of response to psychoactive drugs are valuable in providing practical guidance and in optimizing a treatment regimen. Here we used linear regression analysis to identify treatment-specific predictors of response to therapy with beaded extended-release carbamazepine capsules (CBZ-ERC) (Shire, Wayne, PA, USA) in 600 outpatients with bipolar disorder. Data were obtained from medical charts of subjects who received CBZ-ERC in a private practice setting. Illness severity and improvement were assessed using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. We found that increasing baseline CGI-S scores correlated with lower CGI-I scores (R2=0.01, p=0.009); that is, the higher the baseline CGI-S score, the greater the expected degree of improvement. There was also a correlation between increasing CBZ-ERC dose and improvement in CGI-I scores (R2=0.02; p=0.0004). Moreover, we found that increasing carbamazepine (CBZ) blood concentration correlated with decreases in CGI-I scores (R2=0.12; p=0.025), and that there was a correlation between higher total daily CBZ-ERC dose in mg/kg of body weight and decreases in CGI-I scores (R2=0.01; p=0.038). These findings suggest that bipolar patients with more severe baseline symptoms, on higher CBZ-ERC doses, and with higher CBZ blood levels were more likely to respond to CBZ-ERC treatment.

Hair analysis differentiates chronic from acute carbamazepine intoxication

This is a report of a 12-year-old epileptic child undergoing chronic treatment with carbamazepine who was found comatose. He was considered to have acute severe drug toxicity. Measurement of carbamazepine concentration in the patient's hair segments together with the carbamazepine blood levels were both important in determining the chronic nature of the patient's intoxication. Mantzouranis EC, Bertsias GK, Pallis EG, Tsatsakis AM. Hair analysis differentiates chronic from acute carbamazepine intoxication.

The effects of Cassia auriculata and Cardiospermum halicacabum teas on the steady state blood level and toxicity of carbamazepine

A study was conducted using male Wistar rats as the experimental model, to compare the effects of concurrent administration of herbal tea prepared from dried flowers of Cassia auriculata or aerial parts of Cardiospermum halicacabum and carbamazepine, on (a) steady state serum levels of the prescription drug, and (b) changes in toxicity (as assessed by changes in general behaviour, haematological parameters, and liver and kidney function) that may occur due to drug interaction. Results demonstrate that in rats receiving the Cassia auriculata tea and carbamazepine, the blood levels of the prescription drug were significantly enhanced by 47.1% ( P<0.04), when compared with the levels in animals receiving only carbamazepine for the same time period, with no apparent changes in toxicity. In animals receiving the Cardiospermum halicacabum tea, there were no significant changes in the blood levels of carbamazepine or drug-related toxicity. Cassia auriculata tea has therefore the potential to influence the bioavailability of carbamazepine, and hence its therapeutic actions. Concurrent ingestion of carbamazepine with herbal teas containing Cassia auriculata is therefore best avoided by patients under treatment for epilepsy.

Carbamazepine toxicity after influenza vaccination

Accidental ingestion and drug interaction are known causes of carbamazepine toxicity. Less well recognized is the possibility that influenza vaccination may significantly increase carbamazepine blood levels. Our experience suggests that carbamazepine toxicity can result from influenza vaccination.

Effect of Multiple Dose Omeprazole on the Pharmacokinetics of Carbamazepine

The pharmacokinetics of carbamazepine (CBZ) were studied in 7 patients with duodenal ulcer both before and after 14 days’ treatment with omeprazole (20 mg/day), as this substituted benzimidazole has been shown to alter the pharmacokinetics of some drugs. CBZ serum levels were determined by high pressure liquid chromatography following oral administration of CBZ 400mg. Omeprazole treatment caused increases in CBZ blood levels and significantly prolonged the elimination half-life from 17.2 ± 5.9 hours to 37.3 ± 22.8 hours. Simultaneously, there was an increase in the area under the curve (AUC0-∞) from 382.3 ± 81.1 μg/ml · h to 668.8 ± 241.6 μg/ml · h, while the CBZ clearance was decreased significantly from 20.7 ± 3.4 ml/h/kg to 12.5 ± 3.5 ml/h/kg. Other parameters such as maximum plasma drug concentration (Cmax), time to reach maximum concentration (tmax), and apparent volume of distribution at steady-state (Vss) were, however, not altered by omeprazole treatment. The reduction in clearance and increase in half-life and AUC0-∞ values may be attributed to inhibition of CBZ oxidative metabolism by omeprazole.

Carbamazepine Neurotoxic Reaction After Administration of Diltiazem

A patient with epilepsy controlled by carbamazepine developed a carbamazepine neurotoxic reaction after being given an increased dosage of diltiazem hydrochloride as adjunctive therapy. Abrupt withdrawal of diltiazem reduced the circulating carbamazepine concentration and resulted in an epileptic attack. Awareness of the interaction between diltiazem and carbamazepine and careful monitoring of carbamazepine blood levels is recommended to prevent the dangerous neurotoxic effect associated with this combination.

Comparison of Steady‐State Blood Levels of Two Carbamazepine Formulations

The steady-state plasma level produced by brand-name carbamazepine (CBZ) (Tegretol, Ciba-Geigy) was compared with a generic formulation (Parke-Davis) in 10 subjects with partial epilepsy in a randomized, double-blind, cross-over clinical trial. In addition, seizure frequency and clinical and laboratory signs of toxicity were evaluated. Our results failed to show any difference in CBZ blood levels, seizure frequency, or clinical or laboratory signs of toxicity in patients receiving either the brand-name or generic formulation.

Lithium-carbamazepine versus lithium-neuroleptic prophylaxis in bipolar illness

Fourteen DSM-III diagnosed patients with lithium-resistant bipolar affective disorder treated with a combination of lithium and carbamazepine were followed in a lithium clinic for one year to study the prophylactic benefit and side effects of this drug regimen. Comparison data for the previous year on lithium and neuroleptics showed that for the 9 patients who completed the study, the lithium-carbamazepine regimen was superior to lithium-neuroleptics in decreasing the number of affective episodes and side effects. Carbamazepine blood levels appeared to be a possible contributing factor in the development of side effects.

Tics and Vocalizations in Children Treated with Carbamazepine

Three patients are reported who, following the initiation of carbamazepine therapy for seizure control, either experienced the onset of Tourette's syndrome or a worsening of their tics and vocalizations. Blood levels of carbamazepine were within the therapeutic range, and no patient showed clinical signs of intoxication. Tics and vocalizations did not resolve following discontinuation of carbamazepine therapy. Carbamazepine may trigger the onset of Tourette's syndrome in susceptible patients.

Time-Dependent Kinetics VII: Effect of Diurnal Oscillations on the Time Course of Carbamazepine Autoinduction in the Rhesus Monkey

□ Extensive blood sampling and repeated long-term carbamazepine infusions were carried out in four rhesus monkeys to examine the time course of carbamazepine autoinduction in detail and assess the intraanimal variability in the rate constant of induction. Diurnal oscillations in carbamazepine blood levels were observed during all infusions and these prevented a good data fit for the biochemical model previously proposed for describing the decline in drug blood levels during induction by carbamazepine. An attempt at fitting only selected blood samples to the model resulted in variable (and perhaps questionable) induction rate constants, even in the same animal. Previous variability in calculated induction rate constants may be due to the presence of diurnal oscillations superimposed on the autoinduction phenomenon. It is proposed that the simultaneous expression of diurnal oscillations and autoinduction are the result of effects on drug metabolism at two independent levels.

Hyponatraemia and carbamazepine intoxication

The anticonvulsant, carbamazepine (Tegretol), has an anti-diuretic action. Serum sodium, osmolarity and carbamazepine blood levels were measured in 55 patients and related to symptoms of carbamazepine intoxication. Seven patients had hyponatraemia (serum sodium < 133mmol/l) and hypo-osmolarity; 5 of these were asymptomatic. Serum sodium was inversely correlated with carbamazepine blood levels and hyponatraemia occurred in older patients. Fifteen patients had symptoms of carbamazepine intoxication, 13 had normal serum sodium and osmolarity. Carbamazepine intoxication was considered not to be due to water intoxication.