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%.     

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.     

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。     

癫痫治疗中丙戊酸钠与苯妥英钠或卡马西平的相互作用

丙戊酸钠与苯妥英钠或卡马西平合用治疗各型癫痫90例,丙戊酸钠使苯妥英钠和卡马西平血浓度下降;丙戊酸钠和卡马西平是强有力的肝酶诱导剂,使丙戊酸钠血浓度降低。抗痫药之间的相互作用错综复杂,临床上选择单一用药,尽量避免联合用药。     

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.     

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.     

Effects of the Removal of Phenytoin, Carbamazepine, and Valproate on the Electroencephalogram

We report the EEG changes that occurred on discontinuance of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in patients with active epilepsy. Discontinuation of CBZ was associated with an increase in mean frequency of dominant rhythm and reduction in amount of slow activity. Patients who had a marked increase in seizures on discontinuation of an antiepileptic drug had a slower mean dominant rhythm at baseline than did patients who did not have an increase in seizures. Subsequent EEGs, during and at the end of drug reduction, showed an increase in bursts of interictal epileptiform activity (IEA) and in slow activity in patients who had a marked increase in seizures. The amount of slow activity and IEA did not alter in patients who did not have an increase in seizures. No patients developed photosensitivity.     

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.     

Increased Valproate Serum Concentrations Upon Carbamazepine Cessation

Valproate (VPA) serum concentrations (Cp) were followed in six epileptic mentally retarded patients when carbamazepine (CBZ) was discontinued. VPA Cp significantly increased when CBZ was discontinued. A new plateau of VPA Cp was achieved 4 weeks post-CBZ discontinuation. This time factor is analogous to the autoinduction property of CBZ. Careful VPA Cp monitoring is recommended when CBZ or other enzyme inducing agents are discontinued.     

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.     

Influence of Different Methylxanthines on the Anticonvulsant Action of Common Antiepileptic Drugs in Mice

The protective activity of carbamazepine (CBZ, 60 min before testing), phenobarbital (PB, 120 min), phenytoin (PHT, 120 min), and valproate (VPA, 30 min) alone or concurrent with methylxanthine derivatives was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were administered intraperitoneally (i.p.), and the protection offered by antiepileptic drugs (AEDs) was expressed as ED50 in mg/kg. Caffeine sodium benzoate in doses of 0.0595-0.476 mmol/kg (11.55-92.4 mg/kg) distinctly reduced the anticonvulsant efficacy of PB, in the highest dose tested with an increase in ED50 value from 19.5 to 38 mg/kg. This methylxanthine derivative in the dose range of 0.119-0.476 mmol/kg (23.1-92.4 mg/kg) also efficiently inhibited the protective action of PHT. When combined with caffeine (0.238 and 0.476 mmol/kg), the ED50 of PHT was raised from 12 to 17 and 24 mg/kg, respectively. In doses of 0.238 and 0.476 mmol/kg, caffeine also diminished the efficacy of CBZ and VPA, and at the highest dose tested the methylxanthine elevated the respective ED50s from 13 to 20.5 mg/kg and from 270 to 420 mg/kg. Generally caffeine sodium benzoate (up to 0.476 mmol/kg) did not affect the plasma levels of studied AEDs, and only at 0.476 mmol/kg did it significantly decrease the level of PHT. Among the other methylxanthines, pentoxifylline (0.238-0.476 mmol/kg; 66.3-132.5 mg/kg) and diprophylline (0.952 mmol/kg; 242.1 mg/kg) inhibited the protective potential of PHT and the respective ED50s were raised from 12 to 16.5, 15.5, and 14 mg/kg. No significant alterations in PHT plasma levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of Carbamazepine-10,11-Epoxide, an Active Metabolite of Carbamazepine, with Valproate: A Pharmacokinetic Study

The mechanism responsible for the valproate (VPA)-induced elevation of serum carbamazepine-10,11-epoxide (CBZ-E) levels was investigated in 6 normal subjects who received single oral doses of CBZ-E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d.)]. VPA caused a significant prolongation of CBZ-E terminal half-life (t1/2 from 6.3 +/- 1.2 to 9.0 +/- 2.0 h, mean values +/- SD) and decreased CBZ-E clearance (from 90.6 +/- 18.8 to 63.2 +/- 16.1 ml h-1 kg-1, mean values +/- SD) without affecting CBZ-E apparent volume of distribution (from 0.82 +/- 0.19 to 0.81 +/- 0.24 l kg-1, mean values +/- SD). These findings indicate that VPA impairs the elimination of CBZ-E, presumably by inhibiting its metabolism.     

Effects of Carbamazepine and Phenytoin on EEG and Memory in Healthy Adults

Summary: Using a randomized, double-blind, cross over design, we investigated the effects of carbamazepine (CBZ) and phenytoin (PHT) on memory and spectral EEG components in 15 healthy adults. Each subject was treated with each drug for 1 month, separated by a 1-month washout. Evaluations were conducted at baseline, at the end of each treatment month, and 1 month after the last treatment phase. EEG was collected during an eyes-closed resting condition and a verbal memory activation task. Spectral analysis of the EEG in the nondrug conditions showed that the memory task significantly reduced theta components and increased delta components. As compared with nondrug conditions, the antiepileptic drugs (AEDs) significantly impaired memory performance and produced mild EEG slowing. Memory performance did not differ statistically between the AEDs, but minor differences in spectral EEG components were noted. The results suggest that differences in the cognitive and EEG effects of CBZ and PHT are not clinically significant.     

Cytogenetic Effects of Phenytoin and/or Carbamazepine on Human Peripheral Leukocytes

The cytogenetic effects of phenytoin (PHT) and/or carbamazepine (CBZ) were studied to determine clastogenic potential. Comparative analysis of chromosome breakage and sister chromatid exchange (SCE) was performed between 18 patients with epilepsy receiving PHT and/or CBZ and 10 healthy nontreated controls. These studies failed to detect a significant increase in chromosome aberrations or SCEs in groups of treated individuals as compared with controls. No correlation was observed between the rate of either chromosome damage or SCEs and age, sex, drug blood level, or daily dose. The results indicate no detectable chromosome damaging effects of PHT alone, CBZ alone, or a combination of these two antiepileptic drugs (AEDs).     

Metabolism of Antiepileptic Medication: Newborn to Elderly

Summary: Epilepsy affects individuals of all ages. Regimens of antiepileptic drugs (AEDs) and side-effect profiles differ for infants, children, adults, and the elderly. Thus, the epileptologist must be familiar with the specific changes of AED metabolism with age. In general, metabolic rates are fastest in children; therefore, AED half-lives are shortest in this group. Rates of AED elimination are slowest in neonates, infants, and children. Thus, children need larger dosages, on a mg/kg basis, than adults. The usual phenytora (PHT) dosage in adults is 4–6 mg/kg per day, but children may need a dosage three to five times higher. On the other hand, the PHT dosages in the elderly may need to be 3–4 mg/kg per day to achieve therapeutic levels. Likewise, the half-life of carbamazepine (CBZ) is shortest in children and the elderly. Profiles of metabolites may also be age-specific, a difference of particular importance for valproate (VPA). The relative amount of VPA metabolized to 4-ene is more than twofold less in adults than in children, which may explain the different profile of hepatotoxicity seen by age. The elderly may be more vulnerable to adverse effects of AEDs. Many elderly have neurologic deficits that may render them more vulnerable to neurotoxic effects such as ataxia and cognitive disturbances. Also, low serum albumin concentrations, which result in decreased binding, may mask high serum AED concentrations. The hyponatremia associated with CBZ may be a particular concern in the elderly. Gingival hyperplasia, a concern in children, may not be a problem in the elderly.     

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.     

Effects of Ketamine Anesthesia on Phenytoin Biodisposition

After oral administration (10% suspension in arabic gum, at 500 mg/kg), total phenytoin (PHT) concentrations were measured in the blood and brain of rats anesthetized with ketamine (60 mg/kg, intraperitoneally i.p.) and in a control group that received only PHT. The concentration of PHT in blood and brain was significantly higher in the ketamine than in the control group. At 1, 1.5, 2, and 3 h, increased brain PHT reflected increased blood concentrations. At all times, the plasma protein binding of PHT was similar in both groups. After intravenous (i.v.) administration, instead, at 10 mg/kg, total PHT concentrations were similar in rats anesthetized with ketamine (60 mg/kg, i.p.) and in a control group that received only PHT under mild ether anesthesia. Thus, the main factor involved with the altered PHT biodisposition caused by ketamine anesthesia appears to be increased absorption of the drug.     

Comparing the Cognitive Effects of Phenytoin and Carbamazepine in Long-Term Monotherapy: A Two-Year Follow-Up

Summary: We compared the cognitive effects of randomly prescribed phenytoin (PHT) and carbamazepine (CBZ) therapy on newly diagnosed patients with epilepsy in a 2–year parallel group follow-up study. Fifteen patients were receiving PHT and 16 were receiving CBZ. Neuropsychological assessements were conducted before the treatment and after 6 and 24 months of steady-state drug therapy. Differential effects of PHT and CBZ during follow-up were observed in 3 of 32 measurements. PHT appeared to have negative effects on visually guided motor speed of both hands. In addition, the performance of the PHT group as compared with the CBZ group developed less positively in one visual memory task. The development of mood, as measured by Profile of Mood States (POMS), was quite similar in both drug groups; Tension, Depression, and Bewilderment decreased and Vigor increased during the follow-up. The results suggest that the long-term effects of PHT as compared with thoseof CBZ on cognition are few and restricted mainly to some visually guided motor functions. The effects of PHT on cerebellar function as a possible mechanism for these changes is discussed.     

Intraction of the Anticonvulsant Ameltolide with standard Anticonvulsants

The newly characterized anticonvulsant ameltolide was studied in mice in combination with the standard antiepileptic drugs (AEDs), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). In combination with either PHT or CBZ, ameltolide produced dose-additive effects in the maximal electroshock (MES) test and in the horizontal screen (HS) test for neurologic impairment. The large separation between the doses for the anticonvulsant effects and the neurologically impairing effects (protective index, PI) were maintained as well in the combinations as in the individual compounds. VPA was impotent in the MES test and did not have a clear separation between the doses that produce the anticonvulsant effects and those that are neurologically impairing (low PI). When VPA and ameltolide were combined, the effects were less than additive by isobolographic analysis on both the MES and HS tests. At high oral doses (20 and 40 mg/kg, p.o.), ameltolide produced impairment on the HS test and decreased body temperature. The effects on the HS test were enhanced twofold, whereas the effects on body temperature were not markedly enhanced, by coadministration of the MES ED95 of PHT and CBZ. VPA (MES ED95) appeared to antagonize the temperature-lowering effects of ameltolide. These interaction studies suggest that ameltolide would be safe, with no unexpected effects, when used in epileptic patients concurrently receiving these standard AEDs. These studies also suggest that the effects of ameltolide would be lessened by simultaneous administration of VPA.