Administration Of Oxcarbazepine Research Articles

Chronic Treatment with Oxcarbazepine Attenuates Its Anticonvulsant Effect in the Maximal Electroshock Model in Mice.

The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.

Therapeutic Administration of Oxcarbazepine Saves Cerebellar Purkinje Cells from Ischemia and Reperfusion Injury Induced by Cardiac Arrest through Attenuation of Oxidative Stress.

Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends neuroprotective effects against cerebral or forebrain injury induced by ischemia and reperfusion. However, research on protective effects against ischemia and reperfusion cerebellar injury induced by cardiac arrest (CA) and the return of spontaneous circulation has been poor. Rats were assigned to four groups as follows: (Groups 1 and 2) sham asphyxial CA and vehicle- or oxcarbazepine-treated, and (Groups 3 and 4) CA and vehicle- or oxcarbazepine-treated. Vehicle (0.3% dimethyl sulfoxide/saline) or oxcarbazepine (200 mg/kg) was administered intravenously ten minutes after the return of spontaneous circulation. In this study, CA was induced by asphyxia using vecuronium bromide (2 mg/kg). We conducted immunohistochemistry for calbindin D-28kDa and Fluoro-Jade B histofluorescence to examine Purkinje cell death induced by CA. In addition, immunohistochemistry for 4-hydroxy-2-nonenal (4HNE) was carried out to investigate CA-induced oxidative stress, and immunohistochemistry for Cu, Zn-superoxide dismutase (SOD1) and Mn-superoxide dismutase (SOD2) was performed to examine changes in endogenous antioxidant enzymes. Oxcarbazepine treatment after CA significantly increased the survival rate and improved neurological deficit when compared with vehicle-treated rats with CA (survival rates ≥ 63.6 versus 6.5%), showing that oxcarbazepine treatment dramatically protected cerebellar Purkinje cells from ischemia and reperfusion injury induced by CA. The salvation of the Purkinje cells from ischemic injury by oxcarbazepine treatment paralleled a dramatic reduction in 4HNE (an end-product of lipid peroxidation) and increased or maintained the endogenous antioxidant enzymes (SOD1 and SOD2). In brief, this study shows that therapeutic treatment with oxcarbazepine after CA apparently saved cerebellar neurons (Purkinje cells) from CA-induced neuronal death by attenuating oxidative stress and suggests that oxcarbazepine can be utilized as a therapeutic medicine for ischemia and reperfusion brain (cerebellar) injury induced by CA.

Ictal ECG changes and antiepileptic drug therapy

Abstract Purpose Epileptic seizures may cause severe cardiac arrhythmias. Most people with epilepsy die suddenly and whose death is recognized to a sudden unexpected death in epilepsy (SUDEP). There are controversial reports on the association between polytherapy using antiepileptic drugs and SUDEP. First-line drugs include, in particular, carbamazepine, oxcarbazepine, and lamotrigine, which are sodium channel blockers that may impair heart function. Often a patient requires a combination of antiepileptic drugs Methods 204 patients with epilepsy and were on antiepileptic drugs therapy. The ECG cardiac monitor was implanted in all patients (n=204) and was analyzed together with the preclinical data including age, sex, family history, cardiac risk factors (hypertension, dyslipidemia, diabetes mellitus), heart disease, antiepileptic drug type. Results After a follow-up of 12-month ictal ECG changes (rhythm and conduction disturbances, ST segment abnormalities) were observed in 134 (66%) patients, and only in 70 (34%) – without ictal ECG changes, the average age in these groups was 34,4±9,9 and 36,7±11,8 years (p>0,05). In the group with ictal ECG changes among patients receiving as monotherapy antiepileptic drugs, ictal ECG changes were found in 53.7% of cases, with polytherapy antiepileptic drugs significantly more often – in 71.5% of cases (p<0.05). a reliable association between carbamazepine and changes in sinoatrial and atrioventricular conduction (p=0.01) was significant. In the analyzed group of patients, carbamazepine therapy was also associated with the presence of ictal ST-segment abnormalities (depression/elevation) (p=0.013). A positive association was observed between the administration of oxcarbazepine and development of ictal tachycardia (p=0.04) and ictal right and left bundle branch block, which was observed in 71.4% of cases against the background of oxcarbazepine, significantly more often than with other drugs (p=0.005). Conclusion In agreement with previous publications available in the literature, our results confirm the risk of high-frequency rhythm and conduction disturbances, ST segment abnormalities related to antiepileptic drugs, in particular, carbamazepine and oxcarbazepine and indicates the need of not only cardiological examination before prescribing an antiepileptic drugs, but also a thorough follow-up during the therapy. Patients with ictal ECG changes, primarily rhythm and conduction disturbances, should be under the dynamic control of not only neurologists but also cardiologists and require regular cardiological check-up (ECG, Holter monitoring of the electrocardiogram, echocardiography). Funding Acknowledgement Type of funding source: None

Clinical and Oculographic Analysis of Inferior Oblique Myokymia

A 63-year-old man experienced transient vertical oscillopsia lasting several seconds for 2 months. Examination disclosed paroxysmal excyclotorsion of the right eye, spontaneously or triggered by adduction. Eye movements using 3D video-oculography showed intermittent, monocular phasic movements which consisted of excyclotorsion of the right eye mixed with a small amount of supraduction and abduction, and a tonic movement with excyclotorsion and slight elevation. Orbital and brain MRI was unremarkable. Administration of oxcarbazepine markedly decreased the severity and frequency of the episodes. The oculographic characteristics in our patient may indicate that inferior oblique myokymia may be attributed to aberrant, spontaneous discharges in the inferior oblique motor unit.

Aphasic status epilepticus as the sole symptom of epilepsy: A case report and literature review.

Aphasia is a common symptom encountered by neurologists. However, the presence of aphasia as the sole manifestation of partial status epilepticus is rare. The present study reports a case of aphasic status epilepticus in a 27-year-old right-handed female who presented after the abrupt onset of aphasia, which had persisted for 1.5 days. The patient's medical history included head trauma followed by a craniectomy and cranioplasty. Computed tomography scans revealed a lesion in the patient's left parietal lobe, and an electroencephalogram showed a spike and slow wave pattern in the left hemisphere of the brain during aphasia. The patient's condition improved after the oral administration of oxcarbazepine daily. In the present study it was observed that EEGs were a simple method to diagnose aphasic seizures and therefore EEG recordings should be performed in all cases of unexplained aphasia. In addition, the present study reviewed previously reported cases of aphasic status epilepticus.

Influence of the dual combination of silymarin and (-)-epigallocatechin gallate, natural dietary flavonoids, on the pharmacokinetics of oxcarbazepine in rats

Considering the potential of flavonoids in reversing the P-glycoprotein (P-gp)–mediated multidrug resistance, this work aimed to assess the combined effects of silymarin and (-)-epigallocatechin gallate (EPG) on the pharmacokinetics of the P-gp substrates oxcarbazepine (OXC) and licarbazepine (LIC). Rats were pre-treated intraperitoneally with silymarin (25 mg/kg), EPG (25 mg/kg), silymarin/EPG (12.5/12.5 mg/kg; 6.25/18.75 mg/kg; 18.75/6.25 mg/kg) or verapamil (25 mg/kg, reference P-gp inhibitor) before the intraperitoneal administration of OXC (50 mg/kg). Pre-treatment with dual silymarin/EPG combinations originated peak plasma concentrations of OXC and LIC (pharmacologically active metabolite of OXC) similar to those achieved in the presence of verapamil (positive control). Moreover, the effects promoted by silymarin/EPG combinations on the magnitude of systemic drug exposure to OXC and LIC were also reflected in the corresponding drug levels attained in the brain (biophase). These findings evidence the synergistic effect of silymarin and EPG in enhancing the degree of systemic exposure to OXC and LIC in rats, which occurred in a comparable extent to that observed with verapamil. Hence, our findings support the combination of flavonoid-type P-gp inhibitors and P-gp substrate antiepileptic drugs as a potential therapeutic strategy for the management of pharmacoresistant epilepsy.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

This study was to establish the population pharmacokinetic (PPK) model of pharmacologically active metabolite of oxcarbazepine (OXC) and to estimate PPK parameters for the optimal individuation administration of OXC in Chinese children with epilepsy. The pharmacologically active metabolite, 10-monohydroxy derivative of OXC (MHD)was used as the analytical target for monitoring therapy of OXC. A total of 840 MHD serum samples from 466 children with epilepsy were analyzed using high-performance liquid chromatography with UV detection. Patients' clinical data were retrospectively collected. Population pharmacokinetics analysis was performed using a non-linear mixed-effect model with Phoenix NLME 1.2. Pharmacokinetic parameters were estimated according to a one-compartment model with first-order absorption and elimination. Effects of age,gender, total body weight (TBW), daily doseper weight (DDPW) and use of concomitant antiepileptic drugs (AEDs) were analyzed.Bootstrap and predictive check were used simultaneously to validate the final population pharmacokinetics models. The final PPK model of MHD was: Ka = 0.645 h⁻¹, V(L) = (11.3 + (age - 90.5) x 0.0282 + (TBW - 25.0) x 0.402) x e(0.0689), CL (L/h) = (0.557 + (DDPW - 20.8) x 0.00367 + (gender) x (-0.0636)) x e(0.120). The final PPK model was demonstrated to be suitable and effective by the bootstrap and predictive check. A PPK model of MHD in Chinese children with epilepsy was successfully established. PPK parameters of MHD could be predicted accurately by this model. This model may be very useful for establishing individual dosage guidelines of OXC in Chinese children with epilepsy.

Oxcarbazepine‐induced myoclonic status epilepticus in juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is a frequent idiopathic generalised epilepsy syndrome with typical clinical and EEG features that can usually be controlled by valproate monotherapy. JME may be underdiagnosed or misdiagnosed; in the latter case, it may be mistaken for partial epilepsy. The incorrect diagnosis of JME is likely to result in inappropriate therapy, which may, in turn, worsen the seizures. While a number of studies have documented that carbamazepine aggravates idiopathic generalised epilepsy, few have shown a worsening of symptoms following the administration of oxcarbazepine (OXC). We report the case of a 44-year-old male affected by JME in which the inappropriate use of OXC precipitated a dramatic worsening of myoclonic seizures. In this case, video-EEG monitoring documented myoclonic status epilepticus with positive and negative myoclonus, correlating with repetitive, continuous, rhythmic, generalised polyspike-and-wave discharges. This is the first case of myoclonic status epilepticus induced by OXC in a patient with JME which is clearly documented by video-EEG. A review of the literature with regards to OXC-induced worsening of seizures is also presented. [Published with video sequences].

Pharmacokinetics of the Monohydroxy Derivative of Oxcarbazepine and Its Enantiomers after a Single Intravenous Dose Given as Racemate Compared with a Single Oral Dose of Oxcarbazepine

Oxcarbazepine (OXC) is an antiepileptic drug. In humans, OXC is metabolized via reduction and conjugation. Monohydroxy derivative of OXC (MHD) is the major pharmacologically active component after OXC ingestion. This study was performed to characterize the disposition of the two enantiomers of MHD after oral and intravenous administration and to estimate the bioavailability of MHD after a single oral dose administration of OXC compared to a single intravenous administration of MHD. The study was performed in two parts. In a first pilot study, three intravenous doses were given in an ascending manner (150, 200, and 250 mg of MHD; one subject per dose level) to assess the safety, tolerability, and basic pharmacokinetics. Part two was an open, single-center, randomized, two-way crossover, single-dose trial in 12 healthy adult subjects (n = 6 males and n = 6 females) given OXC orally (one film-coated 300-mg tablet of OXC) and MHD intravenously (250 mg infused over 30 min). Concentrations of OXC and its metabolites were measured by means of high-performance liquid chromatography methods. OXC given as a tablet is completely absorbed in man under fasting conditions. When MHD is given intravenously, (S)-MHD predominates as free compound in plasma. When OXC is administered orally, the ratio of the area-under-the-curve values of (S)-MHD over (R)-MHD equals 3.8, indicating an enantioselective reduction of the prochiral carbonyl group of OXC.

Severe hepatitis associated with administration of oxcarbazepine

Severe hepatitis associated with administration of oxcarbazepine

Pharmaco-EEG-based assessment of the interaction between ethanol and oxcarbazepine

Oxcarbazepine is a representative molecule for a new class of anticonvulsant drugs that can treat alcohol dependence in addition to other disorders. Interestingly, the central mechanism of action in oxcarbazepine is very similar to ethanol, suggesting that these two agents may interact and cause enhanced effects in the central nervous system. In this study, we used a pharmaco-EEG method to examine the influence of oxcarbazepine on the effect of ethanol on the EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex). Oxcarbazepine was administered po as a single dose (20mg/kg or 80mg/kg) or repeatedly at a dose of 40mg/kg/day for 14days. Ethanol was injected iv at a dose of 0.8g/kg 60min after the administration of oxcarbazepine. Ethanol caused an increase in the low frequencies (0.5–4Hz) in the recordings, and it caused a marked decrease in higher frequencies (13–30Hz and 30–45Hz). Oxcarbazepine altered the EEG pattern in rabbits; this interaction was dependent on the dose of the drug and whether it was administered as a single dose or as multiple doses. Oxcarbazepine administered at a lower dose had a synergistic effect with ethanol in the frontal cortex and midbrain reticular formation, and a similar effect was observed in the hippocampus at a higher dose. Changes in EEG recordings after the administration of oxcarbazepine alone were more pronounced after multiple administrations. The drug decreased the sensitivity of the hippocampus to ethanol, an observation that may be important for the treatment of alcohol addiction.

Possible epileptic origin of symptoms in a case exemplifying the sleeper kind of ‘limbic psychotic trigger reaction’

Limbic psychotic trigger reaction (LPTR) includes paroxysmal, motiveless, unplanned felonies, all committed during flat affect, autonomic arousal and a fleeting de novo psychosis. It is considered as a form of non-convulsive behavioural seizures (NCBS). A transient limbic hyperactivation is probably implicated that impairs prefrontal monitoring but preserves memory for the acts. LPTR may, however, not be limited to felonies which have attracted forensic attention. There may exist many more ‘merely’ social misbehaviours, undetected and untreated as a ‘sleeper’ case. This kind of possible undetected LPTR cases, exemplified by a patient who suffers from paroxysmal hallucinations triggering her to attempt to commit infanticide, is presented herein. Our patient had repetitive occurrence of episodes and remission of the symptomatology after the administration of oxcarbazepine, facts that support the epileptic origin of the disorder.

Effect of oxcarbazepine pretreatment on convulsive activity and brain damage induced by kainic acid administration in rats

Temporal lobe epilepsy is one of the most common types of epilepsy. Progress in the understanding and treatment of this type of epilepsy would be greatly facilitated by the availability of an animal model, which reproduced the behavioral and electrographic features of this condition. In this context, kainic acid (KA, 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine) administration causes a syndrome characterized by an acute status epilepticus and subsequent brain damage similar to that in temporal lobe epilepsy of humans. The aim of the present study was to investigate whether oxcarbazepine (10,11-dihydro-10-oxo-5 H -dibenz(b,f)azepine-5-carboxamide), an antiepileptic drug, protects against both epileptic activity and brain damage induced by KA administration. Chronically implanted adult male Wistar rats were polygraphically recorded during 10 continuous hours under 4 different conditions: a) control, b) after KA administration alone, c) after KA administration in oxcarbazepine pretreated animals and d) after the administration of oxcarbazepine alone. Animals treated with KA alone presented behavioral and electrophysiological convulsive activity as well as brain damage. Latency of seizure installation was lengthened significantly and convulsive activity was slightly reduced, however, brain damage was still present in oxcarbazepine pretreated animals. Administration of oxcarbazepine alone induced a hypnotic behavior and brain damage was also present.

The Evaluation of Thyroid Functions, Thyroid Antibodies, and Thyroid Volumes in Children with Epilepsy during Short‐Term Administration of Oxcarbazepine and Valproate

The aim of this study was to evaluate the effects of short-term oxcarbazepine (OXC) and valproate (VPA) monotherapy on thyroid functions in children. Fifty-five newly diagnosed epileptic children with normal thyroid functions (confirmed with the thyrotropin releasing hormone stimulation test) participated in this study. VPA treatment was started in 30 patients and OXC in 25 patients. Serum thyroxine (T(4)), free thyroxine (fT(4)), triiodothyronine (T(3)), free triiodothyronine (fT(3)), reverse T3 (rT(3)), thyroid peroxidase antibodies (TPO-ab), and urine iodine levels were evaluated at baseline and at the third and sixth months of therapy. In the OXC group, serum T(4), fT(4), T(3), fT(3), and rT(3) levels were found to be decreased at the third and sixth months, the differences were significant compared to the baseline values except for fT(3) levels at the third month and fT(4) and rT(3) levels at the sixth month (p < 0.05). At the sixth month, serum T(4) level dropped below the normal reference value in 8 (32%), fT(4) in 5 (20%), T(3) in 4 (16%), and fT(3) in 3 (12%) patients. In the VPA group, mean T(4), fT(4), T(3), fT(3), and rT(3) levels at 3 and 6 months remained similar compared to the baseline values (p > 0.05). Mean serum thyroid stimulating hormone levels increased significantly at the sixth month compared to the baseline values in the VPA group (p < 0.05) while it remained unchanged in the OXC group (p > 0.05). There was no effect of either drug on urinary iodine excretion and serum TPO-ab levels remained in normal ranges throughout the study. In this prospective study, it is documented that children under short-term OXC or VPA therapy showed altered thyroid functions similar to the changes observed after long-term treatment. Although, the clinical significance of these results need to be evaluated with future studies, this observation of altered thyroid functions points out that thyroid functions may need to be monitored closely in children receiving antiepileptic treatment, even in the short-time interval.

Scheme-Based Benzodiazepine Detoxification with Oxcarbazepine

We attempted to evaluate the tolerability and efficacy of the antiepileptic drug oxcarbazepine in benzodiazepine detoxification, by observing several cases. Detoxification followed a predefined dosage scheme. All patients detoxified with oxcarbazepine completed the withdrawal successfully, without withdrawal symptoms. The administration of oxcarbazepine according to the scheme proved to be tolerable. The dosage was sufficient. Though uncontrolled case observations must be interpreted with caution, oxcarbazepine appears to be a promising drug in inpatient benzodiazepine withdrawal. It should be examined in further randomized placebo-controlled studies including long-term follow-ups.

Silent period to transcranial magnetic stimulation: construction and properties of stimulus–response curves in healthy volunteers

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus-response (S-R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900-1800 mg). The S-R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947-0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8+/-3.31 ms (x+/-SEM), -11.51+/-3.31 ms, 11.56+/-0.65%, and 49.82+/-0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69+/-0.72 vs 47.95+/-0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3+/-5.8% at baseline to 59.4+/-10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6+/-42.4 ms to 143.5+/-46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5+/-4.9% to 59.9+/-7.2% and from 29.1+/-6.4% to 34.6+/-6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S-R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Síndrome opercular anterior como manifestación de estado epiléptico no convulsivo

Foix-Chavany-Marie syndrome, or bilateral anterior opercular syndrome, is characterised by facio-pharyngo-glosso-masticatory diplegia with 'automatic-voluntary dissociation', which consists in the abolition of voluntary movements while involuntary movements and reflexes are preserved. It is produced by bilateral involvement of the anterior or frontal opercular region. In adults it is related to ischemic lesions. In childhood it presents congenitally in perisylvian dysplasias and as an acquired disorder in encephalitis or can be episodic in symptomatic or idiopathic epilepsies such as benign rolandic epilepsy. A 13-year-old patient who presented, over five straight days, four episodes of facial dysplegia, anarthria, dysphagia, drooling, paralysis of the upper limbs, while involuntary facial expression was normal and the corneal, cough and gag reflexes were preserved. The first three come to an end spontaneously at 2, 4 and 20 hours, respectively; the fourth episode concluded an hour and a half after onset, following administration of intravenous phenytoin for 5 minutes. Computerised axial tomography and magnetic resonance images of the brain, as well as the interictal electroencephalograms (EEG), were normal. Administration of oxcarbazepine was started but at 8 months was stopped after a normal EEG during nocturnal sleep was obtained. After 15 months, the patient has not presented any more episodes. The paroxysmal character of the disorder together with normal interictal periods, the normality of the neuroimages, and the speedy recovery achieved after the administration of phenytoin support the notion of an epileptic origin. We believe that we are dealing with a bilateral anterior opercular syndrome due to a non-convulsive epileptic state, compatible with the presentation of benign rolandic epilepsy.

Overview of the Clinical Pharmacokinetics of Oxcarbazepine

Oxcarbazepine (GP 47680, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine- 5-carboxamide) is an antiepileptic drug registered worldwide by Novartis under the trade name Trileptal((R)). Trileptal((R))is approved as adjunctive therapy or monotherapy for the treatment of partial seizures in adults and in children. In the US, Trileptal((R)) is approved as adjunctive therapy in adults and in children >/=4 years of age and as monotherapy in adults and in children.Trileptal((R))is currently marketed as 150, 300 and 600mg film-coated tablets for oral administration. A 60 mg/mL (6%) oral suspension formulation has also been registered worldwide.Oxcarbazepine and its pharmacologically active metabolite, 10-monohydroxy derivative (MHD; 10,11-dihydro-10-hydro-carbamazepine; GP 47779) show potent antiepileptic activity in animal models comparable to that of carbamazepine (Tegretol((R))) and phenytoin. Oxcarbazepine and MHD have been shown to exert antiepileptic activity by blockade of voltage-dependent sodium channels in the brain.Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is responsible for the pharmacological effect of the drug. This step is mediated by cytosolic arylketone reductases. MHD is eliminated by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidised to the pharmacologically inactive dihydroxy derivative (DHD). The absorption of oxcarbazepine is complete. In plasma after a single oral administration of oxcarbazepine the mean apparent elimination half-life (t((1/2))) of MHD in adults was 8-9h. Food has no effect on the bioavailability of the highest strength of the final market image tablet (600mg). At steady state MHD displays predictable linear pharmacokinetics at doses ranging from 300 to 2400mg. In children with normal renal function, renal clearance of MHD is higher than in adults, with a corresponding reduction in the terminal t((1/2)) of MHD. Consequently, although no special dose recommendation is needed, an increase in the dose of oxcarbazepine may be necessary to achieve similar plasma levels to those in adults. In patients with moderate to severe renal impairment (creatinine clearance <30 mL/min), the elimination t((1/2)) of MHD is prolonged with a corresponding 2-fold increase in area under the concentration-time curve. Therefore, a dose reduction of at least 50% and a prolongation of the titration period is necessary in these patients. Mild-to-moderate hepatic impairment does not affect the pharmacokinetics of MHD. Based on in vitro and in vivo findings and compared with antiepileptic drugs such as carbamazepine, phenytoin and phenobarbital, oxcarbazepine has a low propensity for drug-drug interactions. In vitro, MHD inhibits the cytochrome P450 (CYP) 2C19 (ki [inhibition constant] = 88 micromol/L). At oxcarbazepine doses above 1.2g, a 40% increase in the concentration of phenytoin and a 15% increase in phenobarbital levels were observed. Oxcarbazepine/MHD at high doses may slightly increase phenobarbital and phenytoin plasma concentrations. Therefore, when using high doses of oxcarbazepine an adjustment in the dose of phenytoin may be required. In vitro, MHD is only a weak inducer of uridine diphospate (UDP)-glucuronyltransferase (UDPGT) and therefore is unlikely to have an effect on drugs that are mainly eliminated by conjugation through the UDPGT enzymes (e.g. valproic acid and lamotrigine). Weak interactions between MHD and antiepileptic drugs that are strong inducers of CYP enzymes have been identified. Carbamazepine, phenobarbital and phenytoin have been shown to reduce MHD levels by 30-40% when coadministered with oxcarbazepine, with no decrease in efficacy. Oxcarbazepine decreases the plasma hormone levels (ethinylestradiol and levonorgestrel) of oral contraceptives and may therefore have the potential to cause oral contraception failure.

Isobolographic and subthreshold methods in the detection of interactions between oxcarbazepine and conventional antiepileptics—a comparative study

Until now, a character of interactions among the antiepileptic drugs (AEDs), in some experimental models of epilepsy, has been determined alternatively with subthreshold and isobolographic methods. In order to elicit the precise and adequate method for evaluating two drug interactions, the comparative study was performed in the maximal electroshock-induced seizure test in mice. In this experimental model, the exact types of interactions among oxcarbazepine (OXC) and conventional AEDs (diphenylhydantoin, phenobarbital, valproate, carbamazepine, and clonazepam) were determined with both methods. Results from the subthreshold method showed a considerable reduction of ED 50 values of clonazepam, diphenylhydantoin and valproate (after administration of OXC at the highest subthreshold dose of 2.5 mg/kg), whilst ED 50s of carbamazepine or phenobarbital were almost unchanged when OXC (2.5 mg/kg) was co-administered with these AEDs. Results from the 2-dimensional (2-D) isobolographic analysis of interactions for a 50% anticonvulsant effect, for three fixed drug dose ratio combinations of 1:2, 1:1, and 2:1, indicate antagonism between OXC and diphenylhydantoin as regards their anticonvulsant (protective) activity. Furthermore, the interactions between OXC and clonazepam occurred either antagonistic (for the fixed-ratios of 1:4 and 1:3) or synergistic (for the fixed-ratio combinations of 1:1 and 2:1) depending on the proportions of used drugs. Remaining interactions between OXC and carbamazepine, OXC and valproate, or OXC and phenobarbital (for the fixed-ratios of 1:3, 1:1, and 3:1) were isobolographically additive for a 50% anticonvulsant effect tested. The 3-dimensional (3-D) isobolographic analysis of interactions between OXC and CZP revealed that the dual character of interactions (antagonistic and synergistic) observed for a 50% anticonvulsant effect (ED 50) was also present for additional drug–dose effects tested, i.e. ED 16 and ED 84. The 3-D isobologram for the combination of OXC with CZP clearly visualized either synergy or antagonism between the drugs in combinations. Distinct differences resulting from two experimental methods prove evidently the superiority of isobolographic analysis over the subthreshold method. The former clearly and adequately detects the exact types of interactions between two AEDs, becoming a potent and powerful paradigm for further studies evaluating the character of interactions among AEDs.

Nefritis intersticial inducida por oxcarbacepina en un paciente con síndrome de hipersensibilidad a fármacos

Antiepileptic drugs (AED) have long been known to have a series of side effects and descriptions of drug hypersensitivity syndrome (DHS) have often linked it with these agents. This is more especially so in the case of those with an aromatic ring, but also in those that lack such a structure. We describe a case of DHS related to the administration of oxcarbazepine (OXC), a ketoanalogue of carbamazepine (CBZ) that has recently appeared on the market in our country, which coursed with interstitial nephritis as the most important clinical manifestation. Our patient developed fever, vomiting, itchy exanthema, kidney failure and biochemical anomalies in the liver after two weeks treatment with this drug. After stopping administration of this anticonvulsant and giving the patient corticoids, the clinical manifestations disappeared and the analytical anomalies began to improve. OXC can give rise to DHS in the same way as other AED with an aromatic ring structure (phenytoin, phenobarbital, primidone, CBZ and probably also lamotrigine) or without an aromatic ring structure (valproic). Interstitial nephritis may be the most significant and serious clinical manifestation of DHS produced by OXC. According to the review of the literature we carried out, to date no descriptions of this association of nephritis caused by OXC in the context of DHS have been reported.