Total and free serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in children with epilepsy

Simultaneous steady-state serum total and free (non-protein-bound) concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured in 68 patients under the age of 21 years with epilepsy (44 males, 24 females; mean age, 11.8 +/- 4.5 years). Thirty patients were maintained on monotherapy with carbamazepine. Mean serum total carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 7.0 +/- 2.4 mg/L (29.5 +/- 10.0 mumol/L) and 1.5 +/- 0.6 mg/L (5.9 +/- 2.6 mumol/L), respectively. Mean serum-free carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 1.3 +/- 0.5 mg/L (5.7 +/- 2.1 mumol/L) and 0.5 +/- 0.3 mg/L (2.2 +/- 1.1 mumol/L), respectively. Binding of carbamazepine and carbamazepine-10,11-epoxide was 81% +/- 3% and 62% +/- 10%, respectively. There was no significant difference in binding between male and female patients or those maintained on monotherapy and polytherapy. Age correlated significantly with carbamazepine binding but not with carbamazepine-10,11-epoxide binding. Free concentrations of carbamazepine and carbamazepine-10,11-epoxide correlated significantly with total carbamazepine and total carbamazepine-10,11-epoxide concentrations, respectively, indicating that the binding capacities of both carbamazepine and carbamazepine-10,11-epoxide are constant at serum total carbamazepine concentrations within the quoted therapeutic range.     

Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide.

We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamazepine (CBZ) and its primary metabolite CBZ-10,11-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P less than 0.01) and the CBZ-E/CBZ ratio increased by 19% (P less than 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.     

The 24 hour variation of salivary carbamazepine and carbamazepine-10,11-epoxide concentrations in children with epilepsy

Variations in carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-EP) concentrations were measured in saliva over 24 hours in 33 children with complex partial seizures and/or generalized tonic-clonic seizures; all patients received CBZ as monotherapy. CBZ varied between 37–104% and CBZ-EP varied between 26–119%. One venous blood sample was obtained simultaneously with the first saliva sample before the morning dose of CBZ. The free fraction of plasma CBZ was 25.5%. Medication side effects are most likely to appear within 3–4 hours of drug intake; therefore, it is advisable to take another sample in children demonstrating time-related side effects. A controlled release formulation of CBZ should minimize the fluctuations of salivary drug levels of CBZ and CBZ-EP.     

Valproic acid-induced carbamazepine-10,11-epoxide toxicity in children and adolescents

The study of 14 children and adolescents shows that the addition of carbamazepine (CBZ) to a basic valproic acid (VPA) therapy can result in unexpectedly high concentrations of carbamazepine-10,11-epoxide (CE) in the serum (up to 13 micrograms/ml). These concentrations were associated with marked side effects, especially vomiting and tiredness. The concentrations of CBZ were within the therapeutic range. Very high CE concentrations can largely be avoided at the commencement of the CBZ treatment if the CBZ dose is slowly increased. But high CE concentrations (4-8 micrograms/ml) associated with side effects can also be reached in later stages during the build up of CBZ treatment and under steady state conditions. The determination of the CE concentration is important when VPA and CBZ are administered together, especially when side effects occur.     

Carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in brain tissue of epileptic children

Carbamazepine (CBZ), carbamazepine-10,11-epoxide (CBZ-epoxide) and phenytoin (DPH) were measured in brain tissue in two epileptic children undergoing temporal lobectomy. The patients had been treated with the anticonvulsants in question for 2 years.
The CBZ concentration in brain tissue was higher or equal to the plasma concentration. Brain/plasma ratio for CBZ was 1.0 and 1.4, respectively (grey substance). Brain/plasma ratio of CBZ-epoxide was 1.0. Concomitant treatment with DPH increased the percentage of CBZ-epoxide relative to CBZ in both brain and plasma. In white brain substance the concentration of CBZ, CBZ-epoxide and DPH was higher or equal to the corresponding concentration in grey substance.
No major age-related differences in the distribution of anti-epileptic drugs between brain and plasma in these two children compared to adult epileptic patients were noted.
A new quantitative thin-layer chromatographic method for the determination of DPH and phenobarbital (PB) in brain tissue and plasma is described.     

Seizure exacerbation and status epileptics related to carbamazepine-10,11-epoxide

Over a 3-year period, we encountered 6 adults whose seizure control unexpectedly deteriorated with the occurrence of partial status epilepticus and daily multiple seizures. Analysis of the case histories and subsequent clinical follow-up for 1 1/2 to 3 years disclosed the following evidence that demonstrates the role of carbamazepine-epoxide in the development of the seizure exacerbation: (1) There were high serum carbamazepine-epoxide concentrations while serum carbamazepine concentrations were lower than or the same as baseline levels; (2) all patients were taking drugs that are known to increase serum carbamazepine-epoxide concentrations; (3) status epilepticus failed to respond to intravenous phenytoin loading; (4) seizure exacerbation in all patients was corrected by withholding carbamazepine dose; (5) seizure exacerbation recurred in 1 patient who resumed the same dose of carbamazepine; and (6) there were no prior status epilepticus or daily multiple seizures despite previous toxicities with other antiepileptic drugs in 3 patients. Our experience shows that inconspicuous elevation of carbamazepine-epoxide levels during polytherapy may precipitate a distinct state of drug toxicity characterized by severe exacerbation of seizures. Mental retardation may be a predisposition to this condition.     

Carbamazepine-induced thrombocytopenia and carbamazepine-10,11-epoxide: A case report

Abstract The case of a patient who developed thrombocytopenia during treatment with carbamazepine (CBZ) is described. The platelet count recovered soon after discontinuation of CBZ. Lymphocyte stimulation test with carbamazepine-10,11-epoxide (CBZ-10,11-EPOX), a major metabolite of CBZ, was positive, although with CBZ it was negative. These findings suggest that CBZ-10,11-EPOX was possibly causative in the pathogenesis of CBZ-induced thrombocytopenia in this case.     

Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations

In order to overcome the problems of interdosage fluctuations of body fluid concentrations of carbamazepine, a slow-release formulation has been developed. In an open, controlled, within-patient study, the diurnal plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 25 epileptic children first treated with conventional carbamazepine tablets (Tegretol) and then with the Tegretol slow-release preparation. The diurnal plasma concentration curves during treatment with the slow-release formulation showed significantly less variation over 24 hours than during treatment with the ordinary preparation, as measured by the fluctuation index. Mean concentration values also differed significantly, which is explained by a somewhat reduced bioavailability (22% less) of the slow-release formulation. There were no differences in efficacy and tolerability between the two formulations, but there was a clear-cut reduction of reported side effects, especially tiredness, on treatment with the slow-release formulation. For that reason, the slow-release formulation should be a major advantage in treating children with epilepsy, in order to avoid interference with cognitive functions. In 12 children, simultaneous measurements of the concentration of carbamazepine and its epoxide in saliva were made and compared with the plasma values. As expected, the concentration curves corresponded, indicating that saliva sampling is an appropriate alternative for monitoring the concentration of carbamazepine. All children remained on the slow-release preparation after the trial and were followed up for 12 months or more.     

癫痫患者单用卡马西平和合用其他抗痉药时卡马西平10,11-环氧化物的血浓度

目的研究癫痫患者单用卡马西平（ＣＢＺ）和合用其他抗痉药时卡马西平１０，１１－环氧化物（ＣＢＺ－Ｅ）的血浓度。方法采用高效液相色谱法（ＨＰＬＣ）对６７例癫痫患者测定稳态时ＣＢＺ和ＣＢＺ－Ｅ浓度。其中３６例接受单一ＣＢＺ治疗；３１例联合其它抗惊厥剂：苯妥因钠（ＰＨＴ）１４例，丙戊酸钠（ＶＰＡ）１７例。结果ＣＢＺ－Ｅ浓度和ＣＢＺ－Ｅ／ＣＢＺ比率在联合治疗组比单一治疗组高，尤其ＣＢＺ＋ＶＰＡ组比单一治疗组显著增高（Ｐ＜０．０１）。结论在ＣＢＺ血浓度监测中，常规ＣＢＺ－Ｅ浓度测定具有较大临床价值     

Carbamazepine and carbamazepine-10,11-epoxide inhibit amygdala-kindled seizures in the rat but do not block their development

The effect of carbamazepine and its -10,11-epoxide on the development of amygdala-kindled seizures and on completed kindled seizures in the rat was evaluated. Neither carbamazepine (15 mg/kg) nor the -10,11-epoxide (15 mg/kg) was capable of preventing the development of amygdala-kindled seizures, although both drugs, at these doses, exerted marked anticonvulsant effects on completed kindled seizures. These data suggest that different phases of kindling are differentially responsive to pharmacological intervention. They also support the conclusion that different mechanisms underlie the acquisition and maintenance of kindled seizures.     

Comparison between premortem and postmortem serum concentrations of phenobarbital, phenytoin, carbamazepine and its 10,11-epoxide metabolite in institutionalized patients with epilepsy

The last premortem serum concentrations of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) and its CBZ-10,11-epoxide metabolite (CE) were compared with the corresponding postmortem serum concentrations in 16 adult patients of an epilepsy centre. Based on complete postmortem examinations, 12 individuals showed a known cause of death (KCD) and four patients succumbed from sudden unexplained death (SUD). The last premortem and the postmortem serum levels of PB (r = 0.991), PHT (r = 0.986), CBZ (r = 0.985) and CE (r = 0.936) were highly correlated. However, the regression analysis indicated that, except for CE, the premortem concentrations were significantly higher than the postmortem concentrations, i.e. 65% for PB, 34% for PHT, and 16% for CBZ. Varying time lapses (4-62 h) between death and serum sampling during autopsy did not significantly influence the ratio of premortem to postmortem serum levels for PB, PHT, CBZ, and CE (p > 0.1). Furthermore we found no significant differences between the premortem and the postmortem serum concentration ratios CE/CBZ. Considering the above variables, the data of SUD and KCD patients were comparable. Postmortem decrease in anticonvulsant serum concentrations, especially for PB and PHT, should be considered in order to avoid misinterpretation in respect to so-called 'subtherapeutic' serum levels and noncompliance in context with SUD or fatal intoxication.     

Carbamazepine-10,11-epoxide in epilepsy. A pilot study

The effects of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, were evaluated in seven outpatients with frequent epileptic seizures. The study included an initial 4-week period with the carbamazepine dose optimized for each patient. Patients were then crossed over, dose by dose, to carbamazepine-10,11-epoxide and followed up for another 4 weeks. Dosing was single blind. The evaluation of the anticonvulsant effect was hampered by marked fluctuations in plasma levels during treatment with carbamazepine-10,11-epoxide. There was, however, no significant change in seizure control. During epoxide treatment, no subjective side effects were reported despite epoxide plasma concentrations up to 57 mumol/L. Neuropsychological assessment revealed a significant improvement in finger motor speed and logical reasoning during the carbamazepine-10,11-epoxide period. Subnormal serum sodium levels in two patients were normalized after switching from carbamazepine to the epoxide. Continued investigations with this active metabolite of carbamazepine in epilepsy are therefore justified.     

国产卡马西平治疗躁狂症不良反应及其与血药浓度关系

用国产卡马西平治疗了符合我国1984年诊断标准的35例躁狂症病人,以HPLC测定血药浓度,用副反应量表记录不良反应。在6周时间内详细观察了不良反应及其与血药浓度的关系,结果发现:64.7％的病人发生了不良反应,常发生在用药初期,多数病人都能耐受,2周后大多数不良反应能自行缓解。不良反应的发生与血药浓度水平有关。常见的不良反应有头昏、恶心呕吐和皮肤反应。     

Effect of viloxazine on serum carbamazepine levels in epileptic patients

The present study describes the interaction between carbamazepine (CBZ) and viloxazine, a recently synthesized antidepressant agent. Seven epileptic patients on chronic anticonvulsant therapy showed a significant (p less than 0.005) increase in steady-state serum CBZ levels (from 8.1 +/- 2.5 SD to 12.1 +/- 2.5 SD micrograms/ml) when viloxazine (300 mg/day) was added to the therapy. The effect was associated with the appearance of mild CBZ intoxication. The symptoms of this intoxication (i.e., dizziness, ataxia, fatigue, drowsiness) disappeared rapidly, and serum CBZ levels decreased to the basal values, when viloxazine administration was stopped.     

The effect of carbamazepine treatment on serum leptin levels

Patients with epilepsy may manifest metabolic adverse effects throughout the course of their management with antiepileptic drugs. Leptin is a hormone that plays a major role in the regulation of feeding and energy expenditure. Leptin has been expected to form a link to weight gain in epilepsy with the use of some antiepileptic drugs. The aim of this study is to evaluate the effect of carbamazepine on body weight and serum leptin levels.This study was conducted in Izmir Tepecik Training and Research Hospital, Neurology Department. 56 epileptic patients who were on continuous carbamazepine monotherapy for at least 6 months before the study and 42 control subjects were included. Serum leptin and insulin levels were measured.Body mass index, leptin and insulin were not significantly elevated in carbamazepine group compared to control subjects (p > 0.05).Our study demonstrated that carbamazepine therapy does not affect significantly body mass index, leptin and insulin. Data regarding the effect of carbamazepine on serum leptin level is limited but the results of these recent studies are correlated with ours. It can be concluded that carbamazepine is a relatively low risky antiepileptic drug in terms of obesity and metabolic syndrome but further studies are needed.     

Thyroid hormone levels in children receiving carbamazepine or valproate

Antiepileptic therapy is associated with alteration of thyroid hormone levels. We evaluated the effect of valproate and carbamazepine therapy on the thyroid hormone profile of epileptic children. Subjects included children aged 2-12 years receiving therapy for at least 6 months. Free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were measured by electrochemiluminescent assay in 30 children receiving carbamazepine, 34 children receiving valproate, and 30 age- and sex-matched control subjects. Groups were similar for age, body mass index, and duration of therapy. Thyroid-stimulating hormone (mean ± S.D.) was 2.67 ± 1.66, 4.53 ± 1.9, and 3.61 ± 1.75 μIU/mL in the control, valproate, and carbamazepine group, respectively (P < 0.001). Free thyroxine was 1.39 ± 0.19, 1.40 ± 0.63, 1.11 ± 0.19 ng/dL (P = 0.009). Free triiodothyronine was 4.03 ± 0.74, 4.14 ± 0.94, 3.92 ± 0.68 pg/mL (P = 0.54). When groups were compared 2 at a time, there was no difference in free triiodothyronine (P > 0.05). Free thyroxine levels in the carbamazepine group were significantly different from valproate (P = 0.015) and control (P = 0.027). Thyroid-stimulating hormone increased with both valproate and carbamazepine compared to control but was significant with valproate (P < 0.001). We conclude that carbamazepine and valproate therapy alters thyroid functions by decreasing free thyroxine levels. Compensation by increase in thyroid-stimulating hormone is better with valproate. The need for monitoring and supplementation should be assessed further.     

Serum lipid levels during carbamazepine therapy in epileptic children

The aim of the study was to evaluate serum lipid levels during carbamazepine therapy in epileptic children. Thirty epileptic children (18 male, 12 female; age range, 30 months to 14 years) with idiopathic or cryptogenic partial or generalized tonic-clonic seizures (13 CPS, 17 GTC) were evaluated for serum lipids at the onset and the third month of carbamazepine therapy. Carbamazepine was started at 10 mg/kg/day. Mean total cholesterol, low-density lipoprotein, very low density lipoprotein, and triglyceride levels significantly increased during treatment (P < 0.05), but mean high-density lipoprotein levels were not statistically significant throughout the study. Carbamazepine treatment alters the serum lipid profile of children in such a way that it could potentially facilitate the development of atherosclerosis.     

Serum carnitine levels during oxcarbazepine and carbamazepine monotherapies in children with epilepsy

Prolonged antiepilepsy drug treatment can result in secondary carnitine deficiency. The effect of oxcarbazepine on carnitine metabolism has not been reported previously. In this study, serum concentrations of total and free carnitine were measured in 20 children with epilepsy treated with oxcarbazepine monotherapy and were compared with 20 children with epilepsy who were taking carbamazepine as monotherapy. The assays were performed between 3 and 6 months of anticonvulsant treatment. The mean values of serum total and free carnitine levels in patients receiving carbamazepine monotherapy were 63.0 +/- 20.7 micromol/L and 49.1 +/- 16.7 micromol/L, respectively. The mean values of serum total and free carnitine levels in patients receiving oxcarbazepine monotherapy were 64.2 +/- 17.4 micromol/L and 50.3 +/- 13.7 micromol/L, respectively. The values were all between normal ranges. No significant difference was observed in the level of total and free carnitine levels between the two groups. Our results suggest that neither oxcarbazepine nor carbamazepine as monotherapy causes carnitine deficiency in otherwise healthy children with primary idiopathic epilepsy.     

The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy

The aim of the present study was to assess the effect of long-term carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB) treatment on serum lipids and apolipoproteins in epileptic children. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TGs) were measured and the LDL-C/HDL-C and TC/HDL-C ratios were calculated in 320 children and adolescents (129 receiving CBZ, 127 receiving VPA and 64 receiving PB) suffering from various types of epilepsy. Additionally, in a subgroup of 181 children (68 CBZ; 78 VPA; 35 PB) apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), HDL2-C and HDL3-C were measured and apoA-I/apoB and HDL2-C/HDL3-C ratios were calculated. Results of the measurements were compared with those of 169 age-and sex-matched healthy controls. None of the variables considered was significantly correlated with time elapsed since start of treatment or with drug concentration in serum. TC and LDL-C serum levels were high in children receiving CBZ or PB and low in those treated with VPA. Serum LDL-C level exceeded 130 mg/dl in 27.9% of CBZ-group, 31.8% of the subjects receiving PB, but only in 7% of those receiving VPA and in 11.8% of control group subjects. CBZ-treated children also showed high HDL-C and HDL3-C values. In the group receiving VPA, HDL2-C, HDL2-C/HDL3-C ratio and apo B were significantly lower than in the control group. Mean apoA-I levels were low in all treated groups: by contrast, in neither group did TGs, VLDL-C levels and TC/HDL-C or LDL-C/HDL-C ratios differ significantly from the corresponding control group. Our results suggest that the effects of long-term AED therapy on lipid profile and, particularly, on apolipoprotein serum levels increase risk of atherosclerosis-related disease. Moreover, these results confirm our previously reported increased risk in CBZ and PB-treated patients.