Conversion from carbamazepine or oxcarbazepine to topiramate in adolescents and adults with epilepsy

Objective – To explore effectiveness, tolerability and changes in quality of life in patients with epilepsy converting to topiramate (TPM) from carbamazepine (CBZ) or oxcarbazepine (OXC) due to insufficient effectiveness and/or tolerability. Methods – A multicenter, open‐label, non‐interventional trial was used to examine patients (≥ 12 years) with epilepsy, changing to TPM monotherapy from baseline mono‐ or combination therapy with CBZ or OXC. TPM was added to the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1–2 weeks, until a final dose between 50 and 200 mg/day was reached. On the basis of clinical judgment, the treating physician decided whether or not the existing AED treatment with CBZ or OXC could then be withdrawn. Type and number of seizures, preferred TPM dose, quality of life (QOLIE‐10 questionnaire), subjective perception of improvement and adverse events (AE) were documented. Results – 140 patients (53.5% women, mean age 47 years) decided to switch to TPM due to insufficient effectiveness (75% of patients) and/or poor tolerability (80%) of the CBZ/OXC treatment. Average duration of follow‐up was 24 weeks with an overall discontinuation rate of 19.3%, mainly due to AEs (12.1%). At study endpoint, the intended shift to TPM monotherapy was achieved in 73% of patients at a median TPM dose of 100 mg/day. A seizure reduction of ≥ 50% was achieved in 91% of patients in the last scheduled period (weeks 12–26); 62% of patients entering that period remained seizure free. Quality of life at endpoint improved significantly when compared with baseline for all domains of QOLIE‐10 (P < 0.001). Most frequent AEs (reported by ≥ 5% of patients) were paresthesia (9.3%), weight loss (7.9%), convulsions (5.7%) and memory disorders (5.0%). Conclusion – In patients with epilepsy, previously not satisfactorily treated with CBZ or OXC, conversion to TPM may result in an improvement in seizure control as well as in quality of life.     

Absence of interaction between oxcarbazepine and erythromycin

When erythromycin (ERY) is co-administrated with the antiepileptic carbamazepine (CBZ), a drug interaction may cause an increase in CBZ plasma concentrations, which can result in CBZ related toxic symptoms. This cross-over study was designated to investigate whether ERY influences the pharmacokinetics of the new antiepileptic oxcarbazepine (OXC) and its metabolites. In 8 healthy volunteers there were no significant differences in AUC, peak plasma concentrations or time to peak concentration when OXC was administered either with or without ERY. The results of this study suggest that OXC may offer an important advantage over CBZ especially when concomitant therapy with ERY is required.     

年龄及联合用药对癫痫患者奥卡西平血药浓度的影响

目的探讨年龄及联合用药对癫痫患者奥卡西平(OXC)血药浓度的影响。方法对110例口服OXC治疗的癫痫患者血浆中OXC活性代谢产物10,11-二氢-10-羟基卡马西平(OHC)浓度进行检测。计算患者血浆OHC浓度剂量比(CDR)=OHC浓度/(OXC剂量/体质量)。以CDR表示患者奥卡西平血药浓度进行相关分析。结果本组患者口服OXC剂量为300~1500 mg/d,平均(709.13±261.67)mg/d;血浆OHC浓度为1.03~25.38μm/ml,平均(11.64±5.73)μm/ml;CDR为0.06~2.75,平均(0.99±0.54)。相关性分析显示,患者血浆OHC浓度与OXC剂量/体质量呈正相关(r=0.461,P0.01);CDR与年龄呈正相关(r=0.548,P0.01);CDR与性别、癫痫发作类型、病程无关(均P0.05)。OXC+肝酶诱导类抗癫痫药物治疗的CDR明显低于OXC单药治疗(均P0.05)。血浆OHC浓度12μm/ml者总有效率(55%)明显低于血浆OHC浓度≥12μm/ml者(90%)(χ2=25.6,P0.01)。结论在300~1500 mg/d剂量范围内,增加OXC给药剂量可增加血浆OHC浓度,提高抗癫痫疗效。低龄、联合肝酶诱导类抗癫痫药物可降低OXC血药浓度,高龄可增高OXC血药浓度。     

Changes in the disposition of oxcarbazepine and its metabolites during pregnancy and the puerperium

PURPOSE: To determine potential changes in the plasma concentrations of oxcarbazepine (OXC) and its metabolites during pregnancy and puerperium. METHODS: Five women receiving OXC monotherapy were followed prospectively during pregnancy and the puerperium. Four women were enrolled in the first trimester, and one woman, 2 weeks before delivery. Steady-state concentrations of OXC, its active R-(-)- and S-(+)-monohydroxy derivatives (MHD), and the additional metabolite carbamazepine-10,11-trans-dihydrodiol (DHD) were measured at regular intervals by an enantioselective HPLC assay. RESULTS. In all samples, S-(+)-MHD was the most abundant compound in plasma and accounted almost entirely for the amount of active moiety (defined as the molar sum of OXC, R-(-)-MHD, and S-(+)-MHD) found in the circulation. The dose-normalized concentrations of active moiety decreased markedly during gestation and, in four of the five patients, increased strikingly after delivery. Plasma concentrations of S-(+)-MHD mirrored closely the levels of the active moiety. Plasma concentrations of the parent drug and other metabolites also tended to decrease during pregnancy and to increase after delivery. CONCLUSIONS: During treatment with OXC, S-(+)-MHD is by far the most abundant active compound in plasma. The concentration of this metabolite as well as the active moiety may decrease markedly during pregnancy and may increase severalfold after delivery. Because of these striking pharmacokinetic changes, the clinical response should be monitored closely in OXC-treated women throughout pregnancy and the puerperium.     

Pharmacokinetics of 10-OH-carbazepine, the main metabolite of the antiepileptic oxcarbazepine, from serum and saliva concentrations

After administration of 600 mg of the antiepileptic oxcarbazepine to 7 healthy volunteers, serum and stimulated saliva samples were collected for the next 72 h. Concentrations of 10-OH-carbazepine, the main metabolite of oxcarbazepine, were determined by an HPLC method. The time-concentration curves showed a median Tmax of 8 h followed by a plateau until 24 h indicating saturable kinetic processes. Based on the curves, the pharmacokinetic parameters were calculated. The half-life of 10-OH-carbazepine in saliva, 13.8 +/- 3.7 (SD) h, was significantly shorter than in serum, 19.3 +/- 6.2 (SD) h. The half-life of 10-OH-carbazepine in serum was inversely correlated to the free fraction, estimated by the ratio saliva/serum concentrations. Calculation of free fraction by this method showed that 53.1 +/- 14.4 (SD) % of 10-OH-carbazepine is unbound in serum. There was a good correlation (r = 0.914) between serum and saliva concentrations of 10-OH-carbazepine from 8-72 h after administration of oxcarbazepine. This finding indicates that saliva concentrations may prove useful, as has been shown for carbamazepine, in therapeutic monitoring of oxcarbazepine treatment.     

Fluctuations of 10-hydroxy-carbazepine during the day in epileptic patients

Oxcarbazepine (OCBZ) is a new antiepileptic drug with a chemical structure similar to carbamazepine. We investigated the daily fluctuations of 10-OH-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of OCBZ, in patients with or without comedication. Twenty-two profiles of (total) serum concentrations of MHD from 18 epileptic patients on a b.i.d. OCBZ regimen were determined at 8.00, 11.00, 14.00, 17.00, 20.00 h (and 22.00 h/23.00 h). A patient was only considered twice if his comedication or OCBZ dosage had been changed. The maximal MHD concentrations were about 33%±14% higher than the minimal MHD concentrations during the day. The free MHD concentrations were determined in 17 profiles. The mean free fraction of MHD was 56.7%±5.5%. In combination with valproic acid the free fraction (64.0%±1.4%) was slightly, but significantly higher (p < 0.05) than in monotherapy (52.3%±0.9%) or in combination (58.0%±2.6%) with other antiepileptic drugs (2 × phenobarbital, 2 × methsuximide, 1 × sulthiame). Further studies are necessary to clarify if the observed fluctuations of MHD are of clinical importance.     

Effects of the antidepressant drug viloxazine on oxcarbazepine and its hydroxylated metabolites in patients with epilepsy

The effects of Viloxazine (VLX, 100 mg b.i.d. for 10 days) on the steady-state plasma concentrations of Oxcarbazepine (OXC), its active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) and the corresponding diol (DHD) were studied in a randomized, double-blind cross-over placebo-controlled trial in 6 epileptic patients stabilized on a fixed dosage of OXC. Administration of VLX resulted in an 11% increase in the plasma concentration of MHD (p = 0.003) associated with a 31% fall in DHD levels (p = 0.0001). Plasma concentrations of unchanged OXC were unaffected by VLX. No changes in seizure frequency nor signs of drug toxicity were observed during the study. Although VLX may inhibit the conversion of MHD to the inactive diol, the interaction is unlikely to be of clinical significance.     

Transplacental passage of oxcarbazepine and its metabolites in vivo

PURPOSE: The purpose of this study was to investigate human fetal exposure to oxcarbazepine (OCBZ) in vivo. METHODS: Transplacental passage and placental tissue concentrations of OCBZ and its metabolites were determined. Maternal venous blood, cord blood, and placental tissue samples from 12 mothers using OCBZ during pregnancy alone or in combination with other antiepileptic drugs were collected. Samples were analyzed with high-performance liquid chromatography. RESULTS: Maternal venous concentrations of OCBZ and its major metabolites were at same range as cord blood concentrations (OCBZ in maternal serum, 0.19 +/- 0.16 microg/ml, and in cord serum, 0.21 +/- 0.19 microg/ml; 10-hydroxy-10,11-dihydrocarbamazepine (10-OH-CBZ) in maternal serum, 5.69 +/- 2.49 microg/ml, and in cord serum, 5.23 +/- 1.44 microg/ml; 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (10,11-D) in maternal serum, 0.29 +/- 0.22 microg/ml, and in cord serum, 0.28 +/- 0.14 microg/ml). OCBZ (0.17 +/- 0.16 microg/g placental tissue), 10-OH-CBZ (3.49 +/- 1.34 microg/g placental tissue) and 10,11-D (0.25 +/- 0.11 microg/g placental tissue) were detected in the placental tissue. The amount of OCBZ detected from placental tissue was 0.01% of the daily dose. CONCLUSIONS: OCBZ, like other antiepileptic drugs, is transferred significantly through the placenta in humans.     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Efficacy comparison of oxcarbazepine and levetiracetam monotherapy among patients with newly diagnosed focal epilepsy in China: A multicenter,open‐label,randomized study

AimsThis multicenter, open‐label, randomized study (Registration No. ChiCTR‐OCH‐14004528) aimed to compare the efficacy and effects of oxcarbazepine (OXC) with levetiracetam (LEV) as monotherapies on patient quality of life and mental health for patients with newly diagnosed focal epilepsy from China.MethodsPatients with newly diagnosed focal epilepsy who had experienced 2 or more unprovoked seizures at greater than a 24‐h interval during the previous year were recruited. Participants were randomly assigned to the OXC group or LEV group. Efficacy, safety, quality of life, and mental health were evaluated over 12‐week and 24‐week periods.ResultsIn total, we recruited 271 newly diagnosed patients from 23 centers. Forty‐four patients were excluded before treatment for reasons. The rate of seizure freedom of OXC was significantly superior to that of LEV at 12 weeks and 24 weeks (p < 0.05). The quality of life (except for the seizure worry subsection) and anxiety scale scores also showed significant differences from before to after treatment in the OXC and LEV groups.ConclusionsOXC monotherapy may be more effective than LEV monotherapy in patients with newly diagnosed focal epilepsy. Both OXC and LEV could improve the quality of life and anxiety state in adult patients with focal epilepsy.     

Recommendations on the clinical use of oxcarbazepine in the treatment of epilepsy: a consensus view

Extensive clinical use and a series of clinical trials have shown that oxcarbazepine is a valuable antiepileptic drug for the treatment of adults and children with partial onset seizures both in initial monotherapy, for conversion to monotherapy and as adjunctive therapy. The clinically recommended titration scheme for all forms of therapy in adults is to start with 150 mg/day at night and to increase by 150 mg/day every second day until a target dose of 900-1200 mg/day is reached. If necessary, one can go faster and start with up to 600 mg/day and titrate with weekly increments of up to 600 mg/day. In children, treatment can be initiated with 8-10 mg/kg/day body weight in two to three divided doses. Dosage can be increased by 8-10 mg/kg/day in weekly increments if necessary for seizure control. Hyponatremia (serum sodium <125 mmol/l) can develop gradually during the first months of oxcarbazepine therapy in approximately 3% of patients with a previously normal serum sodium. However, there is no need to measure baseline serum sodium concentrations unless the patient has renal disease, is taking medication which may lower serum sodium levels (such as diuretics, oral contraceptives or nonsteroidal anti-inflammatory drugs) or--in rare cases--has clinical symptoms of hyponatremia. During oxcarbazepine maintenance therapy measurement of serum sodium levels should also be considered if medications known to decrease sodium levels are added or symptoms of hyponatremia develop. Oxcarbazepine does not appear to have any clinically notable effects on other safety parameters such as renal and liver function or haematological test results. In summary, oxcarbazepine is a safe and well tolerated antiepileptic drug for partial epilepsy.     

奥卡西平和碳酸锂治疗双相障碍躁狂发作患者的对照研究

目的：比较奥卡西平和碳酸锂治疗双相障碍躁狂发作的疗效和安全性。方法：70例双相障碍躁狂发作患者随机分为奥卡西平组和碳酸锂组各35例,分别给予奥卡西平和碳酸锂治疗8周。以Bech-Rafaelsen躁狂量表（BRMS）、临床疗效总评量表-病情严重程度（CGI-SI）以及治疗中出现的症状量表（TESS）评定疗效及不良反应。结果：两组治疗后BRMS、CGI-SI评分均较治疗前显著下降（P〈0.05或P〈0.01）;两组间比较差异无统计学意义（P〉0.05）;两组不良反应均为轻度。结论：奥卡西平治疗双相障碍躁狂发作的疗效与碳酸锂相当,不良反应轻。     

奥卡西平治疗癫癎的临床观察

目的观察奥卡西平(OXC)治疗癫疒间部分性发作/继发全面性强直-阵挛发作(PS/SGTCS)或特发性全面性强直-阵挛发作(GTCS)的疗效、耐受性和安全性。方法61例PS/SGTCS或GTCS患者,其中40例新诊断癫疒间和未经正规治疗的患者进入OXC单治组;而21例长期先后应用过多种抗癫疒间药治疗者进入OXC加治组。成人OXC起始量均为150 mg每晚1次,维持剂量(600~2 400)mg/d,分2次服用;儿童起始量(4~5)mg/kg每晚1次,维持剂量(30~40)mg/(kg.d)。进行自身对比开放性观察,同时分析单治组与加治组24周内的疗效、不良反应、耐受性和安全性。结果本组总有效率和显效率分别为62.3%和54.1%,控制率为49.2%,累积退出率为24.6%,3例(4.9%)失访,因不良反应和经济原因退出12例(19.7%),其中2例(3.3%)因皮疹退出。最常见的不良反应:乏力6例;头昏、头痛、嗜睡各5例;恶心、皮疹各2例。结论OXC治疗PS/SGTCS或GTCS的疗效明显,不良反应轻,耐受性好,安全性高。     

Effects of the antiepileptic drugs on peripheral nerve function

Objective –  We aimed to compare the effects of antiepileptic drugs and provide findings of peripheral nerve impairment using standard electrophysiological techniques.
Materials and methods –  Young adult outpatients with epilepsy on monotherapy for no less than 6 months with carbamazepine (CBZ), valproic acid (VPA), oxcarbazepine (OXC) and topiramate (TPM) were examined. Patients who had any other disease that could effect nerve conduction studies and who had neuropathic symptoms were excluded.
Results –  Each group contained 15 patients and 20 healthy subjects were examined as the control group. Prolonged latency of median sensory nerve ( P  =   0.004), ulnar sensory nerve ( P  =   0.01) and sural nerve ( P  =   0.003) with a diminished nerve conduction velocity was observed in the CBZ group ( P  =   0.014, P  =   0.002, P  =   0.025, respectively). No correlation was found between VPA, OXC and TPM and the nerve conduction studies ( P  >   0.05).
Conclusions –  Valproic acid, oxcarbazepine and topiramate don't have effects on nerve conduction studies. Mild electrophysiological changes contribute to carbamazepine therapy.     

Effects of kynurenine metabolites on the electrocorticographic activity in the rat

Summary. We examined the effects of kynurenine metabolites administered into the right cerebroventricle (1 μmol) on the electrocorticogram (ECoG) of rats to establish the role of kynurenines on brain function. Kynurenine, anthranilic acid, quinaldic acid, xanthurenic acid or 8-hydroxyquinaldic acid showed no effect on ECoG throughout the recording period of 4 hours. 3-Hydroxykynurenine had a transient suppressive effect on the ECoG, while kynurenic acid caused a slight suppression of ECoG activity. 3-Hydroxyanthranilic acid (3-OH-An), a metabolite of 3-hydroxykynurenine, induced spike discharges with a long latency (60–230 min). 3-OH-An is thought to be metabolized to o-aminophenol, 3-methoxyanthranilic acid, quinolinic acid, 2-ketoadipic acid and picolinic acid. Among 3-OH-An metabolites, only o-aminophenol induced spike discharges several minutes after administration, lasting for 60 min. On the other hand, quinolinic acid suppressed ECoG, though 3-methoxyanthranilic acid, 2-ketoadipic acid and picolinic acid had no effects on ECoG. These electrocorticographic findings suggest that 3-OH-An may induce spike discharges after it is metabolized in the brain to o-aminophenol. Accepted December 18, 1997; received May 28, 1997