Carbamazepine Versus Phenobarbital for Partial Onset Seizures in Children

Thirty-nine children were treated with either phenobarbital (PB) or carbamazepine (CBZ) for newly diagnosed partial onset seizures. Drug selection was randomized in 33 subjects. Parents and the psychologist evaluating the child were blind to drug identity. Psychometric and behavioral evaluations were done at intake and at 6- and 12-month follow-ups. There were no significant differences between drugs in effect on behavior or cognitive function. CBZ caused more systemic problems. There was a trend toward better seizure control with CBZ, but this was not statistically significant. Although individual children in each group had changes in behavior or cognitive status, neither group changed significantly, in either acute or chronic follow-up.     

Combined Administration of Carbamazepine and Phenobarbital: Effect on Anticonvulsant Activity and Neurotoxicity

Despite the trend towards single drug therapy of epilepsy, patients resistant to monotherapy are commonly treated with more than one antiepileptic drug. As part of an investigation on the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between carbamazepine and phenobarbital on the toxicity/efficacy ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain to exclude possible pharmacokinetic interactions from the analysis. A purely additive interaction was found for the anticonvulsant as well as for the neurotoxic effect of the drugs. The combination of carbamazepine and phenobarbital has therefore no advantage over each drug alone in this model. Based on these and previous results, there is no experimental evidence in favor of any combination between the four main drugs against partial seizures, i.e., carbamazepine, phenytoin, phenobarbital, and primidone.     

The Penetration of Phenobarbital in Generalized and Focal Penicillin-Induced Epileptic Brain of the Cat

The penetration of phenobarbital (PB) into cerebral tissue was determined in cats rendered epileptic by parenteral penicillin and in cats with focal penicillin-induced epilepsy. The results were compared with those from normal controls. In both kinds of experimental models of epilepsy, PB penetration was impaired, although a gradual and progressive accumulation of the drug in the brain tissue was observed in all three groups of cats (binding occurring from time 30 min on). Similar to the events with other substances, such as carbamazepine, the prolonged epileptic activity may have contributed to the impaired penetration of PB, because of severe metabolic alterations secondary to seizures. The present data confirm previous reports indicating that epileptic seizures alter the pharmacokinetics of drugs.     

Chronic Carbamazepine Treatment Increases Brain Adenosine Receptors

The effect of carbamazepine on adenosine receptors in vitro has been well documented, with findings from several groups showing that therapeutic doses of this drug are sufficient to inhibit binding to the major portion of adenosine receptors in brain. In this study, we describe the effects of chronic carbamazepine on central adenosine receptors from several areas of rat brain using [3H]diethylphenylxanthine [( 3H]DPX) and [3H]cyclohexyladenosine [( 3H]CHA) as ligands. Carbamazepine was administered to rats orally in the diet at doses of 2.25 g/kg of diet and 5.0 g/kg of diet for periods of 3 and 11 days, respectively. Carbamazepine-treated animals displayed higher levels of adenosine receptors in virtually all brain areas tested, most of which reached significance in the 11-day treatment group. Scatchard analysis revealed increases in the number of receptors. There was no change in peripheral and central type benzodiazepine receptors or beta-adrenergic receptors in the carbamazepine-treated animals. Therefore, carbamazepine treatment in vivo appears to upregulate adenosine receptors, suggesting that this drug may act as an adenosine antagonist.     

Neuroocular Side Effects of Carbamazepine and Phenobarbital in Epileptic Patients as Measured by Saccadic Eye Movements Analysis

The effect of carbamazepine (CBZ) and phenobarbital (PB), alone and in association, on the function of specific brain structures was studied in chronically treated epileptic patients by means of saccadic eye movements (SEMs) analysis. The relationship between daily fluctuations of CBZ plasma levels and the occurrence of intermittent side effects was also evaluated. All treatments produced a significant impairment (p less than 0.001) of SEM function as compared with a group of controls. SEM abnormalities appeared to change in relation to daily fluctuation of CBZ plasma levels. When the SEM parameters were considered separately, PB showed a significantly (p less than 0.001) more relevant sedative effect, whereas both drugs appear to produce the same effect on cerebellar and pontine functions. Although impairment of SEM function was most likely far from reaching clinical significance, it represents important information for the clinician.     

Interactions of Phenobarbital and Phenytoin with Carbamazepine and Its Metabolites' Concentrations, Concentration Ratios, and Level/Dose Ratios in Epileptic Children

Summary: The effects of phenytoin (PHT) or phenobarbital (PB) comedication on the concentrations, concentration ratios, and level/dose ratios of carbamazepine (CBZ) and its metabolites were investigated. The hetero-induction effects of CBZ metabolism by PHT or PB were clearly demonstrated. Serum CBZ level/dose ratios in patients with CBZ polytherapy were decreased while CBZ- l0,11-epoxide (CBZ-E) and trans -l0,11-dihydroxy-10, 1-dihydro-CBZ (CBZ-H) concentrations were increased as compared with those of patients receiving CBZ alone. The concentration ratios of CBZ-H/CBZ and CBZ-E/ CBZ were also greater in patients receiving CBZ +PHT or CBZ+PB than in patients receiving CBZ alone. In addition, positive correlations between serum PHT concentration and CBZ-H/CBZ or CBZ-E/CBZ concentration ratios were observed. There were no significant differences in CBZ-H/CBZ-E concentration ratios, the free fractions of CBZ and its metabolites, and CBZ-E or CBZ-H 1eveYdose ratios among the three groups of patients. Because this approach investigates the in vivo relation between the substrates and products of the enzymes involved in CBZ biotransformation, more detailed information about the drug interactions was obtained. The results suggest that the PHT has a potent induction effect on CBZ epoxidase, whereas PB is a moderate inducer.     

Clinical Side Effects of Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate During Monotherapy in Children

The rate of onset of side effects was examined in 392 pediatric outpatients who received long-term monotherapy with phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), or valproate (VPA) for epilepsy or febrile convulsions. The severity of side effects (based on need to alter treatment), the nature of each drug's most common side effects, and the doses and plasma levels of occurrence were recorded. Our results show that usually accepted therapeutic ranges are well tolerated. Indeed, although some form of side effect occurred in 50% of patients, treatment had to be changed in only 18% and the drug had to be stopped in only 7%. In decreasing order, the rates for side effects were PHT (71%) greater than PB (64%) greater than CBZ (43%) greater than VPA (43%) greater than PRM (29%). Serious side effects requiring withdrawal of treatment occurred at the following rates: PHT (10%) greater than VPA (8%) greater than PRM (8%) greater than PB (4%) greater than CBZ (3%). Among our patients, the best tolerated antiepileptic drug (AED) was CBZ, and the least tolerated was PHT. Behavioral disorders were most common with PB, neurologic disorders with PHT, digestive tract disorders with VPA, and gingival hyperplasia and hirsutism with PHT. Behavioral disorders involving excitement seen with PB and PRM occurred most commonly at low plasma levels. Behavioral disorders involving depression seen with PB and VPA, those involving excitement seen with PHT and VPA, and digestive disorders seen with VPA occurred particularly when plasma levels were high.     

Incidence of Drug-Induced Aggravation in Benign Epilepsy with Centrotemporal Spikes

PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is characterized by an excellent prognosis. Drug therapy is necessary in only a minority of patients. Carbamazepine (CBZ) and phenobarbital (PB) have been reported to cause electroclinical aggravation in some cases. The incidence of drug-induced aggravation in BECTS has never been established. METHODS: We retrospectively studied 98 consecutive cases of BECTS, examined at the Centre Saint Paul between 1984 and 1999; 82 patients had received one or more treatments, often successively and in association. RESULTS: We found only one case of electroclinical aggravation with CBZ among 40 patients exposed to CBZ (35 in monotherapy, five in polytherapy). An additional case showed a marked EEG aggravation on CBZ + PB among 14 patients taking PB (nine with monotherapy and five with polytherapy), and PB was apparently responsible. No patient treated with valproate or benzodiazepines showed aggravation. CONCLUSIONS: Aggravation of BECTS caused by antiepileptic drugs happens only rarely. There is a minor risk of aggravation with CBZ and also probably with PB. Drug-induced aggravation may occur only during certain periods coinciding with spontaneous worsening of BECTS.     

Phenobarbital prophylaxis of post traumatic epilepsy

Phenobarbital (PB) was tested for its efficacy in averting post-traumatic epilepsy (PTE) in patients with non-missile head injuries. The protocol envisaged the administration of PB throughout a period of two years in randomly assigned doses ranging from 0.5 to 1.5 and from 1.6 to 2.5 mg/kg/day. The study included neurologic examination, EEG and plasma PB levels. Ninety patients, 83 of whom with serious head injury, followed the prescribed treatment for the entire period. Two adult patients manifested seizures 5 and 10 months after the trauma. They were being treated with doses over 1.5 mg/kg/day. Another patient had a seizure six months after the end of the prophylaxis. Low doses of PB and monitoring permitted a reduction of side effects. The low incidence of PTE indicates that PB has an efficient prophylactic effect. The results also show that a low dosage has a favourable effect.

---

Sommario è stata indagata l'efficacia di differenti dosi di fenobarbital (PB) nella profilassi dell'epilessia post-traumatica. Il protocollo prevedeva la somministrazione di PB in quantità comprese fra 0.5 e 1.5 e fra 1.6 e 2.5 mg/kg/die, assegnate in modo randomizzato indipendentemente dall'entità del trauma, per un periodo di due anni. La valutazione neurologica, EEG e dei livelli plasmatici di PB erano assicurati a tutti i pazienti. 90 pazienti, 83 dei quali con trauma cranico grave, seguirono il trattamento prescritto per l'intero periodo. Due presentarono crisi rispettivamente dopo 5 e 10 mesi dal trauma. Entrambi erano trattati con dosi superiori a 1.5 mg/kg/die. Un altro paziente ebbe una crisi sei mesi dopo il termine del trattamento. Questi risultati indicano che il PB svolge un'efficace prevenzione dell'epilessia post-traumatica e che un effetto favorevole può aversi anche con dosi non elevate.

     

Nocturnal Sleep and Daytime Somnolence in Untreated Patients with Temporal Lobe Epilepsy: Changes After Treatment with Controlled-Release Carbamazepine

Summary: Purpose: To define sleep disturbances in patients with temporal lobe epilepsy (TLE) and explore the association between carbamazepine (CBZ) therapy, sleep, and daytime somnolence.
Methods: We recorded nocturnal polysomnography and measured subjective and objective daytime somnolence in a group of newly diagnosed TLE patients, who had no evidence of anatomic brain lesion on neuroimaging and had never been treated before. Recordings were performed at baseline, after the initial administration of 400 mg CBZ-controlled release (CR) and after 1 month of treatment (400 mg twice daily b.i.d.). The findings were compared with those of a group of young healthy volunteers, both at baseline and after the first administration of CBZ. The chronic effect of CBZ-CR treatment was evaluated only in TLE patients.
Results: At baseline, nocturnal sleep patterns of TLE patients did not show marked alterations when the influence of seizures, cerebral lesions, and drugs had been ruled out. In both the TLE and the control groups, initiation of CBZ therapy provoked a reduction and a fragmentation of rapid eye movement (REM) sleep and an increase in the number of sleep stage shifts. In the TLE group, these effects were almost completely reversed after 1 month of treatment, and no significant difference was noted between baseline condition and long-term follow-up. With regard to daytime sleepiness, initial administration of the drug caused an increase in objective sleepiness only in the control group. Subjective sleepiness was higher in the control group than in the TLE group but was not modified by the drug.
Conclusions: We conclude that CBZ-CR has negative effects on REM sleep during initial administration but chronic treatment does not significantly modify nocturnal sleep or daytime somnolence.     

Absence Seizures and Carbamazepine in Adults

Summary: Carbamazepine (CBZ) therapy was associated with development of absence seizures in 4 adults with generalized epilepsy. Two patients had new appearance of absence seizures and 2 patients had recrudesence of remote absence seizures. The seizures abated after discontinuation of CBZ therapy or addition of ethosuximide (ESM) in 1 patient intolerant of valproate (VPA).     

Intravenous Phenytoin and Phenobarbital: Anticonvulsant Action, Brain Content, and Plasma Binding in Rat

14C-phenytoin or 3H-phenobarbital were given through indwelling jugular catheters to 65 rats. Anticonvulsant activity was tested by the maximal electroshock seizure test and was correlated with brain concentrations of phenytoin or phenobarbital. Free and total plasma drug levels were determined by equilibrium dialysis. The median effective cerebral phenytoin concentration (EC50) was 10.5 microM/kg (95% fiducial limits, 8.2 to 12.4) 3 min after infusion compared with 10.2 microM/kg 30 min after infusion. The EC50 of phenobarbital was 8.2 microM/kg (6.7 to 9.3 microM/kg) 3 min after infusion. Cerebellar concentrations were equivalent to cerebral concentrations for all rats (r = 0.98). Three minutes after infusion, cerebral:plasma free ratio of phenytoin was 3.73 +/- 0.71 (+/- S.D.); the plasma protein bound:free ratio, 3.70 +/- 0.98. For phenobarbital, the cerebral:plasma free ratio was 0.72 +/- 0.10; the plasma protein bound:free ratio, 0.63 +/- 0.12. Since the EC50 values of phenytoin 3 or 30 min after infusion did not differ, onset of anticonvulsant effect clearly occurred as soon as adequate brain concentrations were attained. Phenobarbital was effective 3 min after infusion, and although much higher free plasma levels were necessary, effective brain concentrations were similar to those of phenytoin. Brain content paralleled plasma protein binding, both being high for phenytoin and low for phenobarbital.     

Carbamazepine Therapy and LongTerm Prognosis in Epilepsy of Childhood

Sixty-seven of 90 patients (74% who had been treated with carbamazepine (CBZ) alone were seizure-free for greater than 3 years. The EEG of the patients given CBZ monotherapy was more often normal in those without neurologic abnormalities other than mental retardation or a genetic predisposition. The prognosis of patients with partial seizures secondarily generalized was poorer than that of the other patients. Patients without mental retardation more often had monotherapy CBZ. The lowest blood level of CBZ for maintenance was considered to be 4 micrograms/ml, although the therapeutic blood level was between 6 and 12 micrograms/ml. Most of the side effects were mild.