Cross-Reactive Skin Eruption with Both Carbamazepine and Oxcarbazepine

Summary: Oxcarbazepine (OCBZ), a 10-keto derivative of carbamazepine (CBZ) has been reported to have a similar range of efficacy and fewer unwanted effects than CBZ since it is a prodrug for the monohydroxy derivative (MHD). A cross-reactivity of only 1 in 4 has been reported between OCBZ and CBZ. For these reasons, we tried OCBZ with 3 consecutive patients with poorly controlled epilepsy who had had a therapeutic response to CBZ but in whom CBZ was discontinued because of serious skin reaction. Each patient had a similar skin response after exposure to only 600–900 mg OCBZ, which suggests a need to practice caution when substituting OCBZ for CBZ in patients known to have serious skin reaction to CBZ.     

Oxcarbazepine (GP 47.680): A Possible Alternative to Carbamazepine?

A double-blind randomized crossover design trial of carbamazepine (CBZ) and oxcarbazepine (OCBZ) was performed with 48 in-patients with epilepsy. All were stabilized on polytherapy including CBZ and had at least two seizures per week. CBZ was replaced by the trial medication. Each trial period started with a titration, followed by a 12-week steady state. Concomitant medications were kept constant during the trial. The criteria for assessment were seizure fit frequency and severity; tolerability; hematology and blood chemistry; plasma levels of antiepileptic drugs; EEG; cardiovascular parameters; and treatment preference. The following differences regarding OCBZ were detected: 9% reduction of the total number of seizures, with a significant reduction of tonic-clonic (20%) and tonic (31%) seizures; increased alertness and concentration ability in five patients; an allergic skin reaction with CBZ that completely disappeared in two patients while receiving OCBZ; an increase of valproate and phenytoin plasma levels in a number of patients, probably caused by reduced enzyme induction; a slight but significant reduction of serum Na, not causing clinical symptoms; less seizures than in the CBZ period in 25 patients (52%); and a preference for OCBZ in 23 patients (48%). We consider OCBZ at least as effective as CBZ with a slightly better tolerability. In severe cases, the wider therapeutic window might improve seizure control.     

The Regulation of Serum Sodium After REeplacing Carbamazepine with Oxcarbazepine

PURPOSE: To evaluate changes in serum electrolyte balance and underlying regulatory mechanisms in 10 male patients with epilepsy 2 and 6 months after replacing long-term carbamazepine (CBZ) monotherapy with oxcarbazepine (OCBZ) monotherapy. Arginine vasopressin (AVP) is thought to be most important underlying mechanism of CBZ-related hyponatremia via direct or kidney tubular mechanisms. Furthermore, AVP is as well hormonally regulated by the renin-angiotensin-aldosterone system and atrial natriuretic peptide (ANP). METHODS: The medication of the patients was changed from CBZ to OCBZ. Serum electrolytes, creatinine, albumin, aldosterone, and the N-terminal fragment of ANP (NT-proANP) concentrations were measured before and 2 and 6 months after the change in the medication. RESULTS: The mean serum sodium level diminished after the medication was changed. Serum sodium levels decreased below the reference range in two (20%) patients during OCBZ medication. Serum sodium levels decreased altogether in four patients, and remained unaltered in six patients. Serum aldosterone levels increased in the six patients whose serum sodium concentrations did not decrease, but no increase was found in the patients with decreased sodium levels during OCBZ medication. Serum NT-proANP levels decreased in all patients. CONCLUSIONS: Serum sodium levels decrease after replacing CBZ with OCBZ. The low serum NT-proANP concentrations appear to reflect the decreased serum sodium levels, but a compensatory aldosterone response may prevent the development of hyponatremia in some patients during OCBZ medication.     

Hepatotoxic Reactions Associated with Carbamazepine Therapy

Hepatotoxic reactions in patients receiving carbamazepine (CBZ) therapy have been reported, and some have been considered fatal. We present two patients with hepatic dysfunction secondary to CBZ therapy. Liver biopsies were compatible with hepatotoxic damage, and the symptoms were reversible with medication withdrawal. Our patients are representative of those in the literature, most of whom have granulomatous hepatitis and sometimes have associated cholangitis. The patients with fatal reactions differed clinically and pathologically from the others, and may represent a different entity. The clinical syndrome resembles a viral hepatitis. Elderly patients seem to be particularly susceptible and their hepatic function should be monitored closely when CBZ therapy is initiated.     

Oxcarbazepine: Mechanisms of Action

Summary: The antiepileptic drug (AED) oxcarbazepine (OCBZ) and its rapidly formed 10-monohydroxy metabolite (MHD) protect against electroshock-induced tonic hindlimb extension in rodents (ED₅₀ 14–21 mg/kg p.o.). Both stereoisomers of MHD also protect. As with carbamazepine (CBZ), these findings suggest clinical efficacy against generalized tonic-clonic and, to some extent, partial seizures. OCBZ (IC₅₀ 5 × 10⁸ M ), MHD (IC₅₀ 2 × 10^-8 M ) and CBZ (IC₅₀ 6 × 10^-7 M ) limit the frequency of firing of sodium-dependent action potentials by cultured mouse central neurons and reduce V _mix progressively in a use-dependent manner at concentrations below therapeutic plasma concentrations in OCBZ-treated patients. This suggests that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OCBZ. Blockade of penicillin-induced epileptiform discharges in hippocampal slices by MHD and its stereoisomers was diminished when the potassium channel blocker 4-aminopyridine was added to the bath fluid. This indicates that additional mechanisms of action, e.g., an effect on potassium channels, might be clinically important. In addition, both stereoisomers are equally responsible for the antiepileptic activity of the racemate, i.e., MHD, and are therefore likely to play a therapeutic role. Such actions could confer broad clinical utility on OCBZ.     

Liver Enzyme Induction and Serum Lipid Levels After Replacement of Carbamazepine with Oxcarbazepine

Summary: We evaluated liver P450 enzyme system induction and serum lipid levels in a prospective follow–up study in 12 male patients with epilepsy after replacing carbamazepine (CBZ) medication with oxcarbazepine (OCBZ). Antipyrine_{1 1/2} increased and antipyrine_CL decreased 2 months after the medication was changed, reflecting normalization of liver P450 enzyme system function. Furthermore, serum total cholesterol levels decreased, but serum concentrations of high-density lipoprotein (HDL)-cholesterol and triglycerides (TG) were unchanged. OCBZ may be the preferable antiepileptic drug (AED) with regard to the effects of the medication on lipid metabolism.     

Anticonvulsant Action of Oxcarbazepine, Hydroxycarbamazepine, and Carbamazepine Against Metrazol-Induced Motor Seizures in Developing Rats

Summary: Antimetrazol effects of carbamazepine (CBZ, 5, 12.5, 25, or 50 mg/kg), oxcarbazepine (OCBZ, 5, 10, 30, or 60 mg/kg), and hydroxycarbamazepine (HCBZ, the main human metabolite of OCBZ, 10, 30, or 60 mg/kg) were studied in 7–, 12–, 18–, 25–, and/or 90-day-old laboratory rats. No drug tested affected the incidence of minimal (clonic) metrazol seizures (mMs) in animals aged ≥18 days; in rats aged 7 or 12 days in which mMs are rare under control conditions, the incidence of mMs was increased by lower doses of CBZ and HCBZ. All drugs tested specifically abolished the tonic phase of major generalized tonic-clonic seizures (MMs) in a dose-dependent manner. In addition, CBZ and OCBZ were able to suppress all phases of MMs in the two youngest groups (7-and 12-day-old). There were no marked differences among the three drugs tested (CBZ, OCBZ, and HCBZ) on their action against metrazol-induced seizures during ontogenesis of rats; i.e., all these drugs appeared to possess an identical profile of anticonvulsant action.     

Clinical Experience with Oxcarbazepine

Summary: Controlled studies of oxcarbazepine (OCBZ) and the largest of the open studies of OCBZ were reviewed. The overall results indicated that OCBZ has the same clinical effect as carbamazepine (CBZ) but causes fewer adverse effects. Studies of allergic toxicity seem to indicate that OCBZ may be tolerated in the majority of patients developing allergy towards CBZ. We concluded that OCBZ is a drug of first choice for the treatment of epilepsy.     

Acute Chemical Pancreatitis Associated with Carbamazepine Intoxication

Summary: A 5-year-old mentally retarded child developed laboratory evidence of pancreatitis during accidental acute carbamazepine (CBZ) intoxication. He had been seizure-free with CBZ for 4 years for a seizure disorder with no obvious toxicity. CBZ had been discontinued 5 months before he was admitted to the hospital. After he accidentally ingested a CBZ overdose, he was found vomiting and lethargic. Serum amylase and lipase levels were increased for several days. With supportive treatment and no CBZ, he recovered and serum amylase and lipase levels returned to normal. No other causes of pancreatitis were identified. Therefore, most likely the chemical pancreatitis was associated with the acute CBZ intoxication.     

Clinical Pharmacology and Pharmacokinetics of Oxcarbazepine

Summary: Oxcarbazepine (OCBZ) is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ) but differing in several important aspects, notably metabolism and induction of metabolic pathways. Consequently, OXCB has fewer drug-drug interactions compared with CBZ. Absorption of OCBZ is rapid and complete. In animals it is responsible for the pharmacological effect. In humans, however, the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect. Exposure to the MHD increases dose proportionally, and steady state is achieved after only three or four doses in a twice-daily regimen. When given with food, systemic exposure to MHD increases by about 17%. MHD is eliminated with a half-life of about 8–10 h. About 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. Results suggest that the kinetics of OCBZ should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD; the glucuronide conjugate will, however, accumulate in these patients. The conversion of OCBZ to MHD is catalyzed by reductase enzymes, which are not subject to induction. Furthermore, OCBZ itself does not appear to induce the cytochrome P-450 family in general, although it does induce the P-450IIIA subfamily; which is responsible for the metabolism of estrogens and the dihydropyridine calcium-channel blockers (e.g., nifedipine, felodipine). In patients, linear and dose-proportional kinetics with no autoinduction of metabolism simplify OCBZ dosage adjustment.     

奥卡西平与卡马西平单药治疗儿童部分性癫的对照研究

目的比较奥卡西平与卡马西平单药治疗儿童部分性癫的疗效。方法71例新诊断的儿童部分性癫患者按单双号顺序分为奥卡西平组(35例)和卡马西平组(36例),并给予相应的药物治疗;6个月后进行疗效评价,观察不良反应。结果奥卡西平组和卡马西平组分别有25例及29例完成6个月治疗;脑电图改善率分别为44.0%及44.8%;显效率分别为92.0%及86.2%;不良反应发生率分别为22.2%及41.2%,两组间比较差异无统计学意义(均P>0.05);卡马西平组2例出现严重不良反应。结论奥卡西平与卡马西平单药治疗新诊断的儿童部分性癫均有很好的疗效,不良反应及耐受性相似,但奥卡西平组未见严重的不良反应。     

Oxcarbazepine in Focal Epilepsy and Hepatic Porphyria: A Case Report

PURPOSE: Despite the development of new antiepileptic agents (AEDs), the therapy of epilepsies along with hepatic porphyrias remains difficult. Most AEDs such as carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) may precipitate clinically latent porphyria by inducing hepatic metabolism and increasing hepatic heme synthesis. Actually, only gabapentin (GBP), an AED without any hepatic metabolism, is known as a potential therapy for partial seizures in patients having hepatic forms of porphyria. METHODS: We present the case of a 28-year-old man with porphyria cutanea tarda (PCT) who has had pharmacoresistant epilepsy with complex partial and secondarily generalized seizures since early childhood. Despite having undergone several AED therapies over the years, no seizure-free interval had been observed. Only CBZ could cause a seizure reduction, but this treatment had to be discontinued as an elevation of the transaminases as well as pruritus and erythema were noted. The patient was then started on oxcarbazepine (OCBZ), a ketoanalogue of CBZ similar in its pharmacologic mechanism as well as its clinical use, but which, in contrast to CBZ, has only a low hepatic induction of microsomal enzymes. A final maintenance dose four times higher than that of CBZ was prescribed. RESULTS: In the follow-up, the patient stopped having seizures, and his liver functions became normal. CONCLUSIONS: It can be concluded that OCBZ can successfully be administered to patients with hepatic porphyria and focal epilepsy who did not respond to treatment with GBP.     

Non-Monoamine Oxidase Inhibitor Antidepressants and Epilepsy: A Review

The literature dealing with the convulsant effects of the antidepressant drugs of the non-monoamine oxidase inhibitor variety is reviews. It is concluded that most of these drugs do lower the seizure threshold and may precipitate seizures even at normal therapeutic doses. The pathophysiology of antidepressant-induced seizures is discussed, and attention is drawn to biochemical differences in those antideprssants that have the least epileptogenic potential or may even be anticonvulsant. The clinical difficulties regarding administration of antidepressant drugs to epileptic patients are mentioned, and some practical advice is offered.     

Possible Interaction Between Oxcarbazepine and an Oral Contraceptive

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.     

Antiepileptic Drug Treatment After Temporal Lobe Epilepsy Surgery: A Randomized Study Comparing Carbamazepine and Polytherapy

Temporal lobectomy is an effective treatment in selected patients with medically intractable temporal lobe epilepsy (TLE). Postoperative antiepileptic drug (AED) treatment guidelines have not been established, and patients are often treated with polytherapy postoperatively. We prospectively randomized 40 patients undergoing temporal lobectomy to monotherapy with carbamazepine (CBZ, 20) or to continuation of their presurgical polytherapy (20) to assess the efficacy and safety of each regimen during the first year after operation. No significant differences between groups were noted with respect to seizure recurrence rate and type or time of recurrence. Patients in the polytherapy group had a 30% incidence of drug-related side effects as compared with only 10% in the CBZ group. These results suggest that after temporal lobectomy for intractable epilepsy, patients can be safely treated with CBZ monotherapy and that treatment with multiple AEDs is not necessary.