A Comprehensive Study of the Relation Between Serum Concentrations, Concentration Ratios, and Level/Dose Ratios of Carbamazepine and Its Metabolites with Age, Weight, Dose, and Clearances in Epileptic Children

Summary: We made a comprehensive study of the relation between age, weight, carbamazepine (CBZ) dose, total clearance (TC), and intrinsic clearance (IC) and concentrations, concentration ratios, and level/dose ratios of CBZ, carbamazepine-10,11-epoxide (CBZ-E) and trans -10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-H) in a group of epileptic children receiving CBZ monotherapy. Body weight and age showed negative correlations with TC, IC, CBZ dose, and CBZ-E/CBZ and CBZ-HI CBZ concentration ratios, and had positive relation with CBZ, CBZ-E, and CBZ-H level/dose ratios. These results indicate decreased CBZ metabolism with patient maturity. Correlations between CBZ dose with TC, IC, and the concentration ratios of CBZ-E/CBZ, CBZ-H/CBZ-E, and CBZ-H/CBZ were positive. CBZ dose also had negative associations with CBZ and CBZ-E level/dose ratios, indicating dose-dependent autoinduction of CBZ metabolism. Our data suggest that weight, age, and CBZ dose have less influence on epoxidehydrolase activities than on epoxidase activities. The CBZ-E/CBZ concentration ratio can be used as an indicator of the degree of autoinduction of CBZ metdbohn, even in patients receiving CBZ monotherapy.     

Pharmacological Interactions of Mesuximide with Phenobarbital and Phenytoin in Hospitalized Epileptic Patients

In order to study the pharmacological interactions of the anticonvulsant drugs mesuximide (MSM), phenobarbital (PB), and phenytoin (PHT), serum concentrations of N-desmethyl-mesuximide (N-DESM-MSM, the main metabolite of MSM), PB, and PHT were determined in 94 hospitalized patients suffering from petit mal epilepsy. When MSM was administered to patients on stable PB or primidone therapy, the mean concentrations of PB increased by statistically significant amounts of 38 and 40%, respectively. Similarly, the additional administration of MSM caused the mean concentration of PHT to rise by 78%. The data also indicate that patients with PB and/or PHT comedication have higher N-DESM-MSM serum concentrations than patients without comedication. The pharmacological reasons for these interactions are discussed. These studies demonstrate that the disturbing side effects of MSM are often due to the co-medication. A carefully planned therapeutical dose procedure with regular serum level determinations is proposed to avoid or at least reduce the adverse effects of MSM.     

Felbamate Increases Phenytoin but Decreases Carbamazepine Concentrations

Felbamate (FBM), a novel antiepileptic drug, was observed to have opposite effects on the serum concentrations of phenytoin (PHT) and carbamazepine (CBZ). Data from two male subjects who stabilized while they received both PHT and CBZ, with serum concentration fluctuations of less than 20 and 25%, respectively, form the basis of this report. Both patients required a greater than or equal to 20% reduction in PHT dose while receiving 38-40 mg/kg/day of FBM. When FBM was tapered to less than 20 mg/kg/day, a sudden drop in PHT concentrations occurred in both patients. As PHT concentrations rose, CBZ concentrations fell in both patients. The CBZ epoxide to parent ratio increased to 0.46 and 0.39, respectively during FBM treatment. The ratios were 0.18 in both patients when not receiving FBM. CBZ concentrations returned to baseline values after FBM was discontinued. This unusual and unexpected effect of FBM on two standard antiepileptic drugs underscores the need for evaluating pharmacokinetic interactions before major drug trials.     

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.     

Concentrations and Effects of Oral Midazolam are Greatly Reduced in Patients Treated with Carbamazepine or Phenytoin

Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacody-namic aspects of an oral 15–mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean 2 SEM) was only 5.7% (0.60 ± 0.16 vs. 10.5 ± 0.6 μg - min/ml), and the peak midazolam concentration was 7.4% (5.2 ± 1.2 vs. 70.4 ± 9.0 μg/ml) of its value in control subjects (p < 0.001). The elimination half-life (t1/2) of midazolam was 1.3 ± 0.2 h in patients and 3.1 ± 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P-450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.     

Effect of Felbamate on Phenytoin and Carbamazepine Serum Concentrations

Felbamate (FBM) is a novel antiepileptic drug (AED) undergoing clinical trials in the United States. During a double-blind, cross-over clinical trial, patients received concomitant phenytoin (PHT) and carbamazepine (CBZ). Dosages of PHT and CBZ were adjusted to maintain serum concentrations +/- 20 and +/- 25% of baseline values. All patients required a PHT dosage decrease of 10-30% during active FBM treatment to maintain stable concentrations. CBZ serum concentrations decreased significantly in patients receiving active FBM. The mean decrease was 1.3 micrograms/ml and occurred in 30 of 32 patients. Therefore, FBM apparently causes a bidirectional effect on the serum concentrations of PHT and CBZ when all three drugs are taken concomitantly.     

Periodontal Condition of Epileptic Adults Treated Long-Term with Phenytoin or Carbamazepine

The periodontal condition of 40 adult epileptic subjects (mean age 51 years) receiving long-term therapy (mean 18 years) with phenytoin (PHT) or carbamazepine (CBZ) was studied. The subjects completed a questionnaire and underwent clinical and radiologic examination. Patients receiving PHT exhibited the same level of alveolar bone loss as those receiving CBZ. Patients receiving PHT exhibited more units with gingival overgrowth, reflected by the significantly higher number of gingival units with increased probing depth (p < 0.05). The results indicate that long-term PHT does not result in increased risk for alveolar bone loss as compared with CBZ.     

Interactions of Phenytoin and Phenobarbital in Terms of Order and Temporal Spacing of Administration in Monkeys

The present study investigated order and temporal spacing interactions of phenytoin and phenobarbital in terms of plasma levels during multiple dosing in monkeys. Phenytoin at a dose of 30 mg/kg and phenobarbital at a dose of 3 mg/kg were administered separately to 4 animals (control group) by nasogastric intubution daily for 10 days. In four subsequent 10-day periods the drugs were administered together in 4 other animals (interaction group) at different times of the day (immediately following one another, 1/2 hr apart, and 6 hr apart) and in a different order of administration (either phenobarbital first and phenytoin later, or the reverse). Blood samples were obtained on the 5th, 8th, and 10th day of each 10-day period. The plasma data indicated: (a) phenytoin is capable of autoinduction, (b) phenobarbital lowers the levels of phenytoin under the four methods of administration studied here, and (c) phenytoin can affect the levels of phenobarbital. The latter interaction is a function of order and temporal spacing of drug administration.     

苯妥因钠,丙戊酸钠,卡马西平对癫痫患者智力的影响

抗癫痫药物造成认知功能的损害及损害程度至今仍无明确结果。为此，我们对４６例全身性强直一阵挛发作的癫痫患儿进行了服药前后的智力测验，并以１６例健康同龄人对照，以检测苯妥历钠，丙戊酸钠，卡马西平对智力的影响。     

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.     

Effects of Discontinuation of Phenytoin, Carbamazepine, and Valproate on Concomitant Antiepileptic Medication

We report a prospective, controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients), carbamazepine (CBZ) (23 patients), and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT, with no change in CBZ-10, 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%, respectively, on VPA discontinuation, with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation, all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.     

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.     

Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate

Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 +/- 0.93 (mean +/- SEM), decreasing to 0.87 +/- 0.71 with addition of FBM, and 0.82 +/- 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced. FBM clearance decreased an additional 16.5%.     

Effect of Acute and Chronic Terfenadine on Free and Total Serum Phenytoin Concentrations in Epileptic Patients

Terfenadine is a unique H1-receptor antagonist devoid of adverse central nervous system (CNS) effects. Terfenadine is highly protein bound and has been shown to stimulate hepatic microsomal enzymes, making an interaction with phenytoin (PHT) possible. After assuring constant PHT levels for 7 days, 12 epileptic patients were studied with PHT alone, after a single daily dose of terfenadine (60 mg twice daily), and again after 2 weeks of chronic terfenadine therapy. Samples for PHT were drawn over 24 h, and urine was collected for determination of the PHT metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The pharmacokinetic parameters calculated for total and free PHT and HPPH were area under the time concentration curve (AUC), the maximum serum concentration (Cmax), the minimum serum concentration (Cmin), and the percentage of fluctuation between maximum and minimum concentrations. A factor analysis was used to clarify interrelationships. Five dependent variables were found to represent the data. These were assessed by multi-variate analysis of variance (MANOVA); p less than 0.05 was considered significant. No significant differences were observed for any of the parameters for the acute or chronic effects of terfenadine. We conclude that terfenadine does not interfere with PHT.     

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.     

Comparative Effects of Phenytoin and/or Phenobarbital Treatment on Sister Chromatid Exchange

The potential of the widely prescribed antiepileptic drugs (AEDs) phenytoin (PHT) and phenobarbital (PB) to interact with genetic material was tested using sister chromatid exchange (SCE) assay. Thirty adult male patients with epilepsy receiving long-term AED therapy (16 with PHT, 6 with PB, and 8 with combined PHT and PB therapy) and 30 healthy controls were selected for the study of SCE frequencies in peripheral lymphocytes. The patients and controls were carefully screened and matched for sex, age, and smoking habits. All potential probands with exposure to factors known or suspected of affecting the SCE frequencies were excluded. Statistical analyses did not show any significant differences between the SCE rates of PHT- and/or PB-treated patients and controls, indicating a lack of mutagenicity of the tested drugs as expressed by induction of SCE on adult recipients. Smoking, however, affected the SCE levels considerably. The smokers had higher SCE frequencies than the nonsmokers, both among patients and controls. Caffeine consumption was also associated with SCE increases in patients but not in controls.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Inhibition of Carbamazepine and Phenytoin Metabolism by Nafimidone, a New Antiepileptic Drug

When nafimidone (NFM), a new antiepileptic drug, was given to six patients already taking carbamazepine (CBZ) and phenytoin (PHT) as part of a late phase I pilot efficacy trial, it reduced CBZ elimination by 76-87% and reduced PHT elimination by 38-77%. CBZ and PHT levels rose within 24 h after NFM was started, and began to decline within 12 h after NFM was stopped. The inhibitory effect on CBZ metabolism persisted throughout the course of 1 year of long-term follow-up in all five patients who continued with the drug after completion of the pilot study. Inhibition of PHT elimination persisted in three of the patients, but PHT elimination returned to baseline rates in the other two patients during long-term follow-up. The inhibition of CBZ and PHT metabolism is probably due to binding of cytochrome P-450 by NFM or a metabolite and thus inhibition of the hepatic microsomal mixed-function oxidase system.