The authors reported one case of toxic epidermal necrolysis that occurred in the carbamazepine treatment in a 47-year old male patient with aggressive organic mental disorder. This case developed toxic epidermal necrolysis while taking carbamazepine with a dose of 600mg/day. Toxic epidermal necrolysis did not improve after discontiuation of carbamazepine. We reviewed incidence and the natural history of toxic epidermal necrolysis.
Alcoholism ; Carbamazepine ; Cluster Analysis ; Neurocognitive Disorders ; Humans ; Incidence ; Male ; Middle Aged ; Natural History ; Stevens-Johnson Syndrome*

BACKGROUND: Lamotrigne (LTG) is a newly developed antiepileptic drug which has shown to'be effective for medically intractable partial seizures. LTG was recently introduced to Korea but its clinical efficacy has not been investigated yet. METHODS: We assigned 34 medically intractable localization related epileptic patients taking maximally tolerable dose of carbarmazepine(CBZ). The study protocol consisted of 12 weeks of baseline phase, 4 weeks of phase I (drug -adjustment phase) and 8 weeks o f phase II (maintenance of LTG 200mg/day) After phase II, eligible patients entered into long-term therapy. Two patients dropped out during phase II for adverse event (AE) in one, and AE and poor seizure control in the other. RESULTS: Intention to treat analysis of the seizure outcome after 12 weeks of LTG add-on therapy showed mean seizure frequency reduction of 23.6% (p=O.006). More than 50% seizure frequency reduction was seen in 9 of 34 patients (26.4%), which was comparable to the results of previous clinical trials. On the other hand, the incidence of AE were quite high, which was developed in 27 patients. Dizziness with or without blurred vision and/or diplopia were the most common AE and occurred in 64.7%, which improved promptly by either reduction of CBZ or LTG doses. Twenty-two patients entered into long-term therapy and 18 patients showed either maintenance or more. LTG add-on therapy did not show any significant alterations of baseline Lab. Tests. DISCUSSION: LTG was an effective and safe new antiepileptic drug. However, about two-third of our patients developed A. E. similar to CBZtoxicity, which should be carefully considerd for treating patients taking maximally tolerable CBZ therapy. The proportion of patients taking LTG 300mg/day or more was very low in this study, which suggested the racial difference of tolerability to LTG.
Carbamazepine* ; Diplopia ; Dizziness ; Hand ; Humans ; Incidence ; Intention to Treat Analysis ; Korea ; Seizures

OBJECTIVES: To establish a method for the detection of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: The blood samples were treated with 1-butyl-3-methylimidazolium hexafluorophosphate as an extraction solvent. The samples were extracted by ultrasound-assisted extraction and separated by ZORBAX Eclipse Plus C18, 95Å column. The mobile phase A aqueous solution containing 0.1% formic acid and 10 mmol/L ammonium acetate, and mobile phase B mixed organic solvent containing acetonitrile/methanol (V_acetonitrile∶V_methanol=2∶3) were used for gradient elution at the flow rate of 1.00 mL/min. An electrospray ion source in positive mode was used for detection in the multiple reaction monitoring. RESULTS: The linearities of carbamazepine and its metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 10,11-dihydro-10-hydroxycarbamazepine in blood samples were good within the corresponding range, with correlation coefficients (r) greater than 0.995 6. The limits of detection were 3.00, 0.40 and 1.30 ng/mL, respectively. The limit of quantitation were 8.00, 1.00 and 5.00 ng/mL, respectively. The extraction recoveries ranged from 76.00% to 106.44%. The relative standard deviations of the intra-day and inter-day precisions were less than 16%. Carbamazepine and its main metabolite 10,11-dihydro-10,11-epoxycarbamazepine were detected in blood samples of death cases with a mass concentration of 2.71 μg/mL and 252.14 ng/mL, respectively. CONCLUSIONS This method has high sensitivity and good selectivity, which is suitable for the detection of carbamazepine and its metabolites in blood samples, and can be used for carbamazepine-related forensic identifications.
Chromatography, Liquid/methods* ; Tandem Mass Spectrometry ; Methanol ; Carbamazepine/analysis* ; Benzodiazepines/analysis* ; Solvents ; Chromatography, High Pressure Liquid ; Solid Phase Extraction

OBJECTIVETo study the effects of carbamazepine on serum metabolic profiles in rats using nuclear magnetic resonance (NMR) spectroscopy.

METHODSTwenty-four healthy male Wistar rats were randomized into 4 groups (n=6) for daily intragastric administration of high-, medium- or low-dose carbamazepine or distilled water (control) for 7 days. Blood samples were collected from the abdominal aortic under anesthesia after the treatment to determine serum carbamazepine concentration using high-performance liquid chromatography. ¹H nuclear magnetic resonance (¹H NMR) spectra were acquired for pattern recognition analysis. Histopathological changes of the renal and liver tissues of the rats were also examined.

RESULTSSteady-state blood concentration of carbamazepine in high-, medium- and low-dose groups were 14.64 ± 1.41, 8.54 ± 1.19, and 4.56 ± 0.64 µg/ml, respectively. Slight liver swelling was found in high-dose group, but none of the groups showed renal pathologies. Compared with the control group, the high-dose carbamazepine group showed lowered serum concentrations of 1,3-diaminopropane, deoxycorticosterone, 7-dehydrocholesterol, betaine, beta-alanine, L-cystathionine, 4-methyl-2-oxovaleric acid, and creatine with increased levels of saccharides, lactate, succinic acid, acetyl phosphate, and adipic acid. Principal component analysis revealed significant differences of the metabolites between carbamazepine-treated groups and the control group. The metabolic profiles showed no differences in the kinds of metabolites although the concentrations of the metabolites varied between the carbamazepine groups.

CONCLUSIONSCarbamazepine significantly affects metabolism in normal rats. This finding provides evidence for clinical drug monitoring and drug safety of carbamazepine. NMR technique has important values for pharmacodynamic and toxicological evaluation of drugs.

Animals ; Carbamazepine ; blood ; Kidney ; pathology ; Liver ; pathology ; Magnetic Resonance Spectroscopy ; Male ; Metabolomics ; Principal Component Analysis ; Rats ; Rats, Wistar

The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.
Algorithms ; Bayes Theorem ; Carbamazepine ; analogs & derivatives ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; pharmacokinetics ; Models, Biological ; Monte Carlo Method ; Nonlinear Dynamics ; Regression Analysis ; Tacrolimus ; pharmacokinetics

OBJECTIVETo assess bone health in epileptic children who have been treated with carbamazepine (CBZ) or valproate (VPA) by using quantitative ultrasound (QUS) and determining the biochemical indices of bone metabolism, and to provide a proposal to improve quality of life of epileptic children.

METHODSNinety-two epileptic children who had been treated with CBZ or VPA for more than two years were evaluated for bone mineral density (BMD) at the mid-shaft tibia and the distal third of the radius. Biochemical indices of bone metabolism including urine deoxypyridinoline (DPD) and serum osteocalcin (OC), and daily calcium intake were also evaluated. Thirty-five age-matched healthy children were used as controls. Reduced BMD was defined as speed of sound (SOS) Z scores of the mid-shaft tibia and (or) the distal third of the radius less than -0.7.

RESULTSBMD was reduced in epileptic children significantly when compared to the controls (P < 0.05). In addition, a negative correlation was found between the duration of anti-epileptic drugs (AEDs) use and BMD (r(s) = -0.21 - -0.31, P < 0.05), the lowest BMD was observed in those who had been treated for the longest time. The serum values of OC in epileptic children were significantly reduced relative to the controls (P < 0.01), children who took VPA had the lowest value of OC. However, the urine values of DPD showed no significant difference between epileptic and healthy children (P > 0.05); children who took CBZ had the highest value of DPD. Thirty-two epileptic children (35%) and five (14%) sex- and age-matched healthy children had reduced BMD, significant difference was found between them (P < 0.05). Moreover, epileptic children with reduced BMD seemed to have higher body mass index (BMI) (P < 0.05), take less daily calcium intake (P < 0.01), and had longer duration of AEDs (P < 0.01). The two risk factors of having reduced BMD in epileptic children were those who had been treated with AEDs for more than five years and higher BMI, while the protective factor was daily calcium intake.

CONCLUSIONSLong-term use of CBZ or VPA is associated with bone metabolism abnormalities, which include reduced BMD and decreased bone turnover (mainly decreased bone formation). Long-term anti-epileptic therapy is an important factor for impaired bone health in epileptic children, and that low calcium intake and high BMI could be two aggravating factors. QUS is a useful method to evaluate BMD of epileptic children who are on long-term anti-epileptic therapy, and to recognize the status of bone health, in helping to promote bone health and improve quality of life in epileptic children by the use of calcium and vitamin D supplementation.

Amino Acids ; urine ; Anticonvulsants ; adverse effects ; therapeutic use ; Bone Density ; drug effects ; Bone and Bones ; diagnostic imaging ; drug effects ; metabolism ; Calcium, Dietary ; analysis ; Carbamazepine ; adverse effects ; therapeutic use ; Child ; Epilepsy ; drug therapy ; Female ; Humans ; Male ; Osteocalcin ; blood ; Radius ; diagnostic imaging ; Tibia ; diagnostic imaging ; Ultrasonography ; Valproic Acid ; adverse effects ; therapeutic use