Serum Carbamazepine Research Articles

Evaluating Appropriateness of Digoxin, Carbamazepine, Valproic Acid, and Phenytoin Usage by Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) is a useful tool for the optimization of drug therapy. The aim of this retrospective study was to evaluate the appropriateness of carbamazepine, phenytoin, valproic acid, and digoxin therapy by using TDM data. We evaluated the appropriateness of drug usage in 325 patients who received carbamazepine, valproic acid, phenytoin, or digoxin in a large teaching hospital during the period from March 2010 to January 2011. The serum drug levels were measured by cloned enzyme donor immunoassay (CEDIA). A total of 325 TDM tests were performed in this period. In our TDM unit, valproic acid was the most evaluated test among the samples obtained. In 100 valproic acid-treated patients, serum levels in 58 patients (58%) were within the therapeutic range. While 11 patients (11%) had serum levels in the above-therapeutic range, 31 patients (31%) had sub-therapeutic levels of valproic acid: The results of TDM were mostly found in the therapeutic range for carbamazepine. A total of 91 request forms were collected. The overall data show that 64 patients (70.3%) had serum carbamazepine levels within the therapeutic range. In the phenytoin assays, the mean plasma concentrations generally did not reach the therapeutic range. Among the total of 49 blood samples, the highest number of sub-therapeutic levels (65.3%) were detected for phenytoin. Similarly, inappropriate levels of digoxin were established in about half of all cases. This study gives information about the inappropriate usage of digoxin and phenytoin in respect to the results of our TDM practice. Our results suggest that there is a need for interventions to improve the appropriate use of digoxin and phenytoin in patients treated with these drugs.

Interaction profile of Zizyphus jujuba with phenytoin, phenobarbitone, and carbamazepine in maximal electroshock‐induced seizures in rats

The antiepileptic effect of hydroalcoholic extract of Zizyphus jujuba (HEZJ) in experimental seizures was demonstrated earlier. The present study aimed to evaluate the pharmacokinetic and pharmacodynamic interactions of HEZJ with phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) in maximal electroshock (MES)-induced seizures in male Wistar rats. Maximal electroshock (70mA, 9ms pulse width, 0.2s) was used to induce seizures. Blood samples were collected at two time points for estimation of serum PHT, PB, and CBZ levels using high-pressure liquid chromatography (HPLC). Co-administration of HEZJ with the sub-therapeutic doses of PHT, PB, and CBZ exhibited 66.7, 66.7, and 50.0% protection against tonic hind limb extension as compared to 33.3, 33.3, and 50% protection respectively, in the groups treated with PHT, PB, and CBZ alone in their sub-therapeutic doses. Co-administration of HEZJ with the sub-therapeutic doses of these antiepileptic drugs (AEDs) showed significant improvement in cognitive functions as compared to MES group as well as these AEDs alone. A significant increase in glutathione levels and decrease in malondialdehyde levels were observed with pretreatment of HEZJ with the sub-therapeutic doses of these AEDs. Co-administration of HEZJ with PHT, PB, and CBZ did not cause any significant changes in the serum concentrations of these AEDs. The results of the present study indicate that the co-administration of HEZJ with sub-therapeutic doses of PHT and PB potentiated the antiepileptic effect of PHT and PB in MES-induced seizures with no change found in the antiepileptic effect of CBZ.

A new herb–drug interaction of Polygonum cuspidatum, a resveratrol‐rich nutraceutical, with carbamazepine in rats

Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE), an active metabolite. This study investigated the acute and chronic effects of Polygonum cuspidatum (PC), a resveratrol‐rich nutraceutical, on the pharmacokinetics of CBZ in rats and the underlying mechanisms. Rats were orally administered CBZ (200mg/kg) alone and coadministered with a single dose and the 7th dose of PC (2g/kg) in a crossover design. The concentrations of CBZ and CBZE in serum and various tissues were determined by HPLC method. The results showed that PC significantly increased the AUC0-t of CBZ and CBZE, whereas the formation rate of CBZE was decreased. Tissue analysis showed that the concentrations of CBZ and CBZE in brain, liver and kidney were significantly increased by PC. Cell studies indicated that the efflux function of MRP 2 was inhibited by the serum metabolites of PC. In conclusion, PC markedly increased the systemic exposure and brain concentration of CBZ and CBZE through inhibiting the activities of CYP 3A and MRP 2.

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR−/− mice, but not in hypothyroid PXR−/− mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR−/− hypothyroid mice, and this induction was abolished in CAR−/− mice and in and CAR−/− PXR−/− double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR−/− mice and lowest in WT and PXR−/− mice. Hypothyroid WT or PXR−/− mice survived chronic CBZ treatment, but all hypothyroid CAR−/− and CAR−/− PXR−/− mice died, with CAR−/−PXR−/− mice surviving longer than CAR−/− mice (12.3±3.3days vs. 6.3±2.1days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.

Comprehensive analysis of the association of SCN1A gene polymorphisms with the retention rate of carbamazepine following monotherapy for new‐onset focal seizures in the Chinese Han population

The aim of the present study was to investigate whether single nucleotide polymorphisms (SNPs) in the sodium channel a subunit type 1 (SCN1A) gene affect the retention rate of carbamazepine (CBZ) used to treat seizures in Chinese Han patients with epilepsy. In total, 448 patients were genotyped for SNPs selected in the SCN1A gene. The tag SNPs were selected using Haploview version 4.2 software (http://www.broad.mit.edu/haploview/haploview, accessed 18 Sept 2009). Monotherapy with CBZ was administered to patients with new-onset focal seizures. In the present study, the retention rate of CBZ was defined as the percentage of patients with epilepsy who had continued with CBZ treatment in the preceding 3months. Potential confounding variables were analysed to evaluate the risk factors for non-retention. When adjusted for potential confounding factors (e.g. age, sex, body mass index, seizure type etc.), the presence of the A allele of SNP rs3812718 predicted non-retention (P=0.015; odds ratio (OR)=3.122; 95% confidence interval (CI)=1.823-4.893). Beyond 12months of treatment in those that continued with CBZ (retention cohort), analysis of covariance indicated that the maintenance dose (P=0.025) and serum CBZ levels (P=0.021) were significantly higher in carriers of the rs3812718 AA genotype than in those with the GG genotype. The results of the present study indicate that the rs3812718 SNP in the SCN1A gene is significantly associated with the retention rate of CBZ monotherapy in Chinese Han patients with focal epilepsy.

Development of Molecularly Imprinted Polymers (MIPS) nano particles for the selective determination of Carbamazepine in human serum and plasma

A new, simple, rapid, and sensitive solid-phase extraction with molecularly imprinted polymer (SPE-MIP) for determination of Carbamazepine in biological samples was developed. These nano particle polymers were synthesized via a non-covalent molecular imprinting approach through precipitation polymerization method using methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker agent, carbamazepine as a target template molecule and azobisisobutyronitrile (AIBN) as an initiator. The optimal conditions for SPE consisted of conditioning the cartridge using a pH=3.0 water, loading 5.0 ml of the sample under basic aqueous conditions, clean-up using 2×2ml acetonitrile and elution with 3.0 ml methanol. After optimization of SPE procedure, an aliquot of extracted template was injected to the ACE, 5μm 250×4.6 mm analytical column with the mobile phase as the same as elution solvent. This method was used for extraction of carbamazepine from an anticonvulsant aqueous solution and the results revealed an extraction recovery of more than 90%. HPLC chromatograms show an efficient clean up, which supports the potential of MISPE for clean-up of trace amounts of carbamazepine from the drug formulation.

Molecularly imprinted nanoparticles prepared by miniemulsion polymerization as selective receptors and new carriers for the sustained release of carbamazepine

Water-compatible imprinted nanoparticles were prepared for carbamazepine as a template and used for the selective extraction and controlled release of carbamazepine. Assay materials and drug delivery carriers were typically used in aqueous environments, so it is generally preferable to prepare solvent-free molecularly imprinted nanoparticles in water using the miniemulsion polymerization method. The present work investigates a bio-analytical strategy generically applicable to imprinted materials for molecular recognition studies, including equilibrium and non-equilibrium binding, and release experiments, increasing the knowledge of the molecular interactions between the template molecules and imprinted nanoparticles. The results showed that the imprinted nanoparticles exhibited a higher binding level and slower release rate than non-imprinted nanoparticles. The selectivity of imprinted nanoparticles for carbamazepine studied in comparison with an analogue compound, oxcarbazepine, the main metabolite of carbamazepine. The recovery and selectivity of carbamazepine in human serum was determined to be 100%, 1.7 times that of oxcarbazepine. The results indicated that carbamazepine-imprinted nanoparticles are appropriate for serum level determination of the drug in therapeutic range. The template to functional monomer ratio as a key factor controlling the recognition and release kinetic mechanism of imprinted nanoparticles is discussed. The imprinted nanoparticles prepared at the appropriate template to functional monomer mole ratio (2:8) exhibited the best drug affinity (5.1 times higher) and a slower drug release rate due to the interaction of carbamazepine with the imprinted cavities within the nanoparticles. Loaded imprinted nanoparticles as drug reservoirs were able to prolong carbamazepine release, in 1% wt sodium dodecyl sulfate aqueous solution, for more than 8 days.

Analysis of carbamazepine serum by differential pulse voltammetry (DPV) and comparison with fluorescence polarization immunoassay (FPIA): an animal study

Few studies have investigated the value of using an electrochemical method with dropping mercury electrodes to determine carbamazepine level. However, the toxic mercury can result in environmental pollution. In our previous study, we successfully developed a differential pulse voltammetric (DPV) method using a glassy carbon electrode instead of a dropping mercury electrode for the determination of carbamazepine level in standard solutions. In this study, we used the DPV method to determine the serum level of carbamazepine in rabbits. Blood samples were obtained from rabbits which had been fed carbamazepine. The serum concentration of carbamazepine from DPV using glassy carbon electrode and fluorescence polarization immunoassay (FPIA) technique was compared using a correlation test. In addition, DPV and FPIA techniques in carbamazepine detection were evaluated for precision, linearity, and detection limits using a standard solution. The correlation between the carbamazepine concentrations from DPV compared with those by FPIA was good (RSQ = 0.998). In addition, the coefficient of variation (CV) for the DPV technique and the FPIA technique were low. The precision and detection limit for both methods were satisfactory. The DPV method using a glassy carbon electrode can be a potential method for the determination of carbamazepine in serum.

P-175 - Concordance of maintenance treatment patterns for bipolar disorders with current practice guidelines in an outpatient setting

Introduction Wide variations in guideline concordance rates for bipolar disorder have been reported. To the authors' knowledge, no studies have been carried out in Spain. Objective To evaluate whether maintenance treatment patterns for outpatients with bipolar disorders in usual practice are concordant with evidence-based prescription guidelines. Methods Cross-sectional data are being collected, starting June 2011, from outpatients diagnosed of bipolar I or II disorders attended at a Mental Health Center in Bilbao (Spain). Information about their maintenance treatment is reviewed, and labelled as “concordant” or “non-concordant”. Medication considered concordant with current guidelines1,3 are lithium (serum levels 0,6–1,2 mEq/L obtained within the previous 6 months), valproate (serum levels 50–100 μg/mL within the previous 6 months), carbamazepine (serum levels 4–12 μg/mL within the previous 6 months), quetiapine (≥300 mg/d), olanzapine (≥10 mg/d), aripiprazole (≥15 mg/d) and, in bipolar II, lamotrigine ≥100 mg/d. Adjunctive use of other medications is also recorded. To assess concordance when various drugs are combined, at least one of them needs to be within therapeutic dose. Results Hitherto, data from 50 patients have been analyzed (66% females; mean age 52,82 ± 13,35; 68% bipolar I). 60% of them present a concordant treatment; 67,64% in the bipolar I subgroup and 43,75% in the bipolar II. Half of the patients are on antidepressants. Conclusions Despite the still small sample size and need of a multicenter assessment, adherence to guidelines seems suboptimal, mainly respecting bipolar II. Implementing interventions that have proven effective for enhancing evidence-based care and therefore improving outcomes should be considered.

Toxicokinetics and correlation of carbamazepine salivary and serum concentrations in acute poisonings

Saliva is a body fluid which, like serum, can be used for determination of concentrations of certain drugs, both in pharmacotherapy as well as in acute poisonings. The aim of this study was to determine carbamazepine concentrations in both saliva and serum in acute poisoning in order to show if there is a correlation between the obtained values, as well as to monitor toxicokinetics of carbamazepine in body fluides. Saliva and serum samples were obtained from 26 patients treated with carbamazepine and 20 patients acutely poisoned by the drug immediately after their admission in the Emergency Toxicology Unit. Determination of salivary and serum carbamazepine concentrations was performed by the validated high pressure liquid chromatography-ultraviolet (HPLC-UV) method. A significant correlation of salivary and serum carbamazepine concentrations in both therapeutic application and acute poisoning (r = 0.9481 and 0.9117, respectively) was confirmed. In acute poisonings the mean ratio between salivary and serum concentrations of carbamazepine (0.43) was similar to the mean ratio after its administration in therapeutic doses (0.39), but there were high inter-individual variations in carbamazepine concentrations in the acutely poisoned patients, as a consequence of different ingested doses of the drug. In acute poisoning the halftime of carbamazepine in saliva and serum was 12.57 h and 6.76 h, respectively. Our results suggest a possible use of saliva as an alternative biological material for determination of carbamazepine concentrations in therapeutic application and acute poisoning as well, and a possible extrapolation of the results obtained in saliva to serum concentrations of carbamazepine.

カルバマゼピン類似体の交差反応を考慮したアーキテクト<sup>Ⓡ</sup>･カルバマゼピンSTによる血中カルバマゼピン濃度測定に対する評価

カルバマゼピン類似体の交差反応を考慮したアーキテクト<sup>Ⓡ</sup>･カルバマゼピンSTによる血中カルバマゼピン濃度測定に対する評価

Validated High Performance Liquid Chromatographic Method for Simultaneous Determination of Phenytoin, Phenobarbital and Carbamazepine in Human Serum

A high performance liquid chromatographic (HPLC) method for the simultaneous determination of phenytoin (CAS 57-41-0), phenobarbital (CAS 50-06-6, phenobarbitone) and carbamazepine (CAS 298-46-4) is described. The serum was extracted with ethyl acetate, the dried extract was reconstituted in mobile phase and the aliquot was injected. The eluent drugs were detected at 230 nm. The mobile phase consisting of methanol: water: glacial acetic acid mixture (67:33:1, v/v/v) was used at a flow rate of 1 ml/min on C-18 column. The absolute recovery was above 96% of all the three drugs over a concentration range of 0.5-50.0 micrograms/ml. The inter-day and intra-day precision relative standard deviation (RSD) ranged from 0.79-5.13% and 0.11-6.81%, respectively. The method is simple, rapid, accurate and sensitive and is presently used for therapeutic drug monitoring in epileptic patients. The results obtained with this method showed very good clinical correlation.

Successful treatment of carbamazepine poisoning with hemodialysis: A case report and review of the literature

A 48-year-old man was brought to the emergency room after ingesting an unknown amount of carbamazepine. He was unconscious and not responding to the noxious stimuli. He was intubated and was placed on mechanical ventilation because of respiratory insufficiency. Primary detoxification was performed with a gastric lavage and charcoal instillation. His serum carbamazepine level was 25.6 mcg/mL at the time of admission. His computed tomography of the brain was normal. He was managed conservatively but there was no improvement in his neurological status in the next 24 hours. Serum carbamazepine level was repeated and reported to be 28.3 mcg/mL. As there was no improvement in his sensorium and the serum carbamazepine levels remained persistently high, extracorporeal removal of carbamazepine was attempted. As the facility to carry out hemoperfusion was not available immediately, the decision to initiate hemodialysis was taken. After 3 sessions of hemodialysis, his sensorium improved markedly and the carbamazepine level at this time was within the therapeutic range. He was discharged after psychiatry consultation and counseling. We review the literature regarding extra corporeal techniques for the removal of carbamazepine and discuss them in this article.

One-way multiplexed immunoassay strategy for simultaneous determination of multi-analytes by microchip electrophoresis

An integrated microchip electrophoresis (MCE) system with online immunoreaction and laser induced fluorescence (LIF) detection has been developed for simultaneous determination of multi-analytes. In this system, the multiplexed immunoreactions between multiple antibody-immobilized glass beads with analytes and respective fluorescently labeled antigens were performed in a sample reservoir. After online incubation, the immunoreaction solution was injected into a one-way separation channel, and free fluorescently labeled antigens were separated and detected in the separation channel. With the help of glass beads, the immunocomplex can not move into the separation channel, which simplifies the separation of fluorescently labeled antigens. With the use of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) and theophylline (Th) as proof-of-principle analytes, the one-way multiplexed immunoassay could be completed within 20 min, resulting in a response curve over the range of 4.0-400 nM for each analyte. Detection limits (S/N = 3) for the drugs tested were in the range of 1.8 × 10(-9) to 2.5 × 10(-9) M. Compared with the conventional immunoassays, this assay is simple, rapid, sensitive and low cost, and provides an accurate procedure for a multiplex immunoassay. The present method has been applied for the simultaneous determination of PB, PHT, CBZ and Th in human serum, which showed a promise of automated clinical application.

Discordant carbamazepine values between two immunoassays: carbamazepine values determined by ADVIA centaur correlate better with those determined by LC-MS/MS than PETINIA assay

Discordant carbamazepine values as determined by two different immunoassays may be due to different cross-reactivities with the active metabolite carbamazepine 10, 11-epoxide and may cause confusion in interpreting carbamazepine serum levels. In this study, we compared carbamazepine values in samples containing carbamazepine and the epoxide metabolite, as determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and by two commercial carbamazepine immunoassays: the PETINIA and the ADVIA Centaur carbamazepine. Clinical specimens were used for the comparative studies wherein we determined carbamazepine concentrations using the PETINIA, ADVIA Centaur, and LC-MS/MS assays. We observed an excellent correlation between carbamazepine concentrations determined by the ADVIA Centaur and LC-MS/MS methods while carbamazepine values were overestimated using the PETINIA assay. When aliquots of drug-free serum were supplemented with clinically relevant concentrations of the carbamazepine epoxide metabolite, we observed negligible cross-reactivity of epoxide with the ADVIA Centaur assay but over 90% cross-reactivity with the PETINIA assay. We conclude that the ADVIA centaur assay accurately measures carbamazepine concentrations in plasma or serum and that the PETINIA assay significantly overestimates true carbamazepine concentration. Such discordance may cause confusion in interpreting serum carbamazepine levels.

Predictability of individualized dosage regimens of carbamazepine and valproate mono- and combination therapy

Many investigators agree that appropriate rational utilization of therapeutic drug monitoring (TDM) with Bayesian feedback dosage adjustment facilitates epilepsy treatment with carbamazepine (CBZ) and/or valproate (VPA) by increasing the seizure control and safety, as well as by reducing treatment costs. In previous works we have developed and used in clinical practice population pharmacokinetic (PK) models of different dosage forms for VPA and post-induction CBZ behaviour, as well as for combined therapy with CBZ plus another 'old' antiepileptic drug (AED). An important step of external validation is to evaluate how well a procedure of Bayesian individualizing AED dosage regimens based on a proposed population PK model and sparse TDM data 'works', and how helpful it is in real practical clinical settings. The aim of this study was to evaluate the predictability of individualized dosage regimens for monotherapy with CBZ in the post-induction period or with VPA, as well as for CBZ and VPA given as combination therapy based on TDM data of epileptic patients and the earlier developed population models. Four groups of TDM data were analysed using the USC*PACK software for PK/PD analysis: 556 predictions for adult epileptic patients on CBZ monotherapy, 662 predictions for VPA monotherapy, 402 predictions of CBZ serum levels and 430 predictions of VPA serum levels for adult epileptic patients on CBZ+VPA combination therapy. Statistical characteristics of the prediction errors (PE) and weighted PE were used to estimate bias and precision of predictions. Intraindividual and interoccasional variability of predictions were also estimated. This study demonstrated that in most cases of CBZ and VPA monotherapy and combination therapy, predictions of future AED concentrations based on the earlier developed population PK models, TDM data and patient-specific maximum a posteriori probability Bayesian posterior parameter values provided clinically acceptable estimates. Statistical analysis of the residuals demonstrated that the distributions of residual and weighted residual were close to the normal distribution (Kolmogorov-Smirnov test, P > 0·05) and their mean values did not differ statistically significant from zero (no statistically significant bias, P > 0·05) for all groups of predictions. The observed decreased quality of predictions of VPA concentrations during VPA+CBZ combination therapy, especially when CBZ dosages were changed, might well be explained by their PK interactions. For all groups, in linear regression analysis, the observed trend of decreasing of the prediction quality over various future prediction time horizons was considered statistically significant (P < 0·05). Prediction of serum levels further in future was less precise than those closer to the present for a 1·5- to 3·5-year observation period. No bias in predictions was associated with the time horizons. Our validation results suggest good predictive performance of the population models developed earlier, and quite acceptable predictions of future AED serum levels for individualized dosage regimens of CBZ and VPA therapy in real clinical settings.

Enantioselective Assay for Therapeutic Drug Monitoring of Eslicarbazepine Acetate: No Interference With Carbamazepine and Its Metabolites

As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

Hydroxyzine and Cetirizine Interfere With the PENTINA Carbamazepine Assay but Not With the ADVIA CENTEUR Carbamazepine Assay

Because of a published report indicating significant interference of hydroxyzine with the particle-enhanced turbidimetric inhibition immunoassay (PENTINA) carbamazepine assay, we investigated whether such interference can be avoided by using the ADVIA Centaur carbamazepine assay. Both the Dimension Vista analyzer and ADVIA Centaur analyzer are available from Siemens Diagnostics. Aliquots of a drug-free serum pool were supplemented with various concentrations of hydroxyzine or cetirizine (0.05 microg/mL to 20 microg/mL covering therapeutic and toxic levels in serum) followed by analysis using both assays. We observed significant apparent carbamazepine concentrations using the PENTINA assay but no apparent carbamazepine level using the ADVIA Centaur assay. Because crossreactivity should be studied in the presence of the primary analyte, we also prepared a serum carbamazepine pool from patients receiving carbamazepine and then supplemented aliquots of this pool with various amounts of hydroxyzine or cetirizine followed by reanalyzing carbamazepine concentration using both assays. We observed falsely elevated carbamazepine values using the PENTINA assay but no interference was observed using the ADVIA Centaur assay. However, the falsely elevated carbamazepine values using the PENTINA assay were clinically significant at hydroxyzine or cetirizine concentrations expected in patients with severe overdoses with these drugs. We conclude that the ADVIA Centaur carbamazepine assay is free from interference of both hydroxyzine and cetirizine.

Carbamazepine-induced hyperammonemia

A case of carbamazepine-induced hyperammonemia is presented. A 26-year-old man with bipolar disorder, seizures, and mild mental retardation secondary to a traumatic brain injury began treatment with carbamazepine for aggression and seizure control. After three weeks of carbamazepine therapy, the patient arrived at the emergency department (ED) with severe agitation and aggressive behavior. His oral medications included topiramate, carbamazepine, olanzapine, quetiapine, guanfacine, and desmopressin acetate. The patient's medications had been stable for at least six months except for the addition of carbamazepine one month before his arrival at the ED. Upon admission, the patient's vital signs were found to be within normal limits, as were his liver profile results, complete blood count, thyroid-stimulating-hormone level, and serum chemistry panel. His serum carbamazepine concentration was 3.9 microg/mL (reference range, 4-12 microg/mL), and his serum ammonia concentration was 127 microg/dL (reference range, 19-60 microg/dL). Carbamazepine was discontinued upon admission, and the patient was treated with oral lactulose. Since carbamazepine was discontinued and had been prescribed for bipolar disorder, his olanzapine dosage was increased, and trazodone was added at bedtime for insomnia. Of note, the patient had been on carbamazepine therapy one year earlier and had experienced the same adverse event. He had also developed elevated serum ammonia levels while on valproic acid. The patient's serum ammonia level returned to normal by hospital day 4, and he was discharged to his group home. A 26-year-old man with bipolar disorder developed hyperammonemia three weeks after initiating carbamazepine therapy.

Instrumental planar chromatographic method for determination of carbamazepine in human serum

An instrumental planar chromatographic (HPTLC) method for quantification of carbamazepine in human serum was developed using liquid-liquid extraction with dichloromethane, fluorescence activation with perchloric acid 60%/ethanol/water (1:1:1, v/v) and fluorescence detection. Planar chromatographic separation was performed on precoated silica gel F254 HPTLC plates using a mixture of ethyl acetate/toluene/methanol/acetic acid glacial (5:4:0.5:0.5, v/v) as mobile phase. Densitometric detection was done at 366 nm. The method was validated for linearity, precision and accuracy. Linear calibration curves in the range of 3 and 20 ng/microL showed correlation coefficient of 0.998. The intra-assay and inter-assay precision, expressed as the RSD, were in the range of 0.41-1.24% (n = 3) and 2.17-3.17% (n = 9), respectively. The LOD was 0.19 ng, and the LOQ was 0.57 ng. Accuracy, calculated as percentage recovery, was between 98.98 and 101.96%, with a RSD not higher than 1.52%. The method was selective for the active principle tested. In conclusion, the method is useful for quantitative determination of carbamazepine in human serum.