Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in-food protocols

PURPOSE: The present study evaluated the effectiveness of intraperitoneal (IP) injections and oral administration of carbamazepine (CBZ) in food on the frequency of spontaneous motor seizures in rats with kainate-induced epilepsy. The purpose was to develop a convenient drug-in-food approach for continuous, long-term administration of potential antiepileptic drugs (AEDs). METHODS: Single IP injections of CBZ (10-100 mg/kg) were compared to vehicle injections via six AED-versus-vehicle tests using a repeated-measures, crossover protocol. Similar protocols were used with CBZ-containing or control food pellets. RESULTS: CBZ significantly reduced motor seizure frequency at 30 and 100 mg/kg after single IP injections, and these doses completely blocked motor seizures during a 6-h postdrug epoch in 25% and 70% of the animals, respectively. Single administrations of 30 mg/kg and 100 mg/kg CBZ in food also significantly reduced motor seizures, and blocked seizures in 33% and 89% of the rats, respectively. CBZ administered in food three times per day (100 mg/kg x3 CBZ in food) continuously blocked nearly all motor seizures over a 5-day period, and completely suppressed motor seizures in 50% of the animals tested. CONCLUSIONS: CBZ strongly suppresses spontaneous motor seizures, and single doses of CBZ in food are as effective as IP injections in rats with kainate-induced epilepsy. CBZ administered regularly in food continuously blocks nearly all motor seizures, and may provide a relatively simple method to test AEDs in chronic models of epilepsy.     

A once-per-day, drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models

Purpose: Convenient and effective methods for administering potential antiepileptic drugs (AEDs) chronically should facilitate many experiments in animal models of chronic epilepsy with spontaneous recurrent seizures. This proof‐of‐principle study aimed to optimize a once‐per‐day, drug‐in‐food protocol by testing the effect of carbamazepine (CBZ) on the frequency of convulsive seizures in rats with kainate‐induced epilepsy. Methods: Adult male rats were given repeated low‐dose kainate injections until convulsive status epilepticus persisted for >3 h. After the rats developed spontaneous recurrent seizures, food pellets with CBZ (30, 100, or 300 mg/kg/day) were provided once per day in three 2‐week trials (n = 7–9 rats) involving 5 days of CBZ or control treatment, separated by two recovery days within a trial. The total amount of food provided and consumed per day corresponded to a normal caloric diet (60 g/kg/day). Key Findings: When provided once per day, all animals ate the CBZ‐containing food irregularly but continuously throughout the 24‐h day. With this daily feeding protocol, CBZ significantly reduced the frequency of spontaneous convulsive seizures in a dose‐dependent manner. It is important to note that the effect of CBZ was consistent across the 5 days and throughout each day of the trials. With food administered at 9:00 a.m., and blood assayed at 5:00 p.m., higher food levels of CBZ resulted in higher plasma concentrations of CBZ. Significance: This AED‐in‐food protocol is simple, efficient, inexpensive, reliable, and noninvasive; it allows easier long‐term drug administration and is less stressful and more humane than other methods of AED administration.     

Effect of antiepileptic drugs on spontaneous seizures in epileptic rats

The present study investigated whether spontaneously seizing animals are a valid model for evaluating antiepileptic compounds in the treatment of human epilepsy. We examined whether clinically effective antiepileptic drugs (AEDs), including carbamazepine (CBZ), valproic acid (VPA), ethosuximide (ESM), lamotrigine (LTG), or vigabatrin (VGB) suppress spontaneous seizures in a rat model of human temporal lobe epilepsy, in which epilepsy is triggered by status epilepticus induced by electrical stimulation of the amygdala. Eight adult male rats with newly diagnosed epilepsy and focal onset seizures were included in the study. Baseline seizure frequency was determined by continuous video-electroencephalography (EEG) monitoring during a 7 days baseline period. This was followed by a 2-3 days titration period, a 5-7 days treatment period, and a 2-3 days wash-out period. During the 5-7 days treatment period, animals were treated successively with CBZ (120 mg/kg/day), VPA (600 mg/kg/day), ESM (400 mg/kg/day), LTG (20 mg/kg/day), and VGB (250 mg/kg/day). VPA, LTG, and VGB were the most efficient of the compounds investigated, decreasing the mean seizure frequency by 83, 84, and 60%, respectively. In the VPA group, the percentage of rats with a greater than 50% decrease in seizure frequency was 100%, in the LTG group 88%, in the VGB group 83%, in the CBZ group 29%, and in the ESM group 38%. During the 7 day treatment period, 20% of the VPA-treated animals and 14% of the CBZ-treated animals became seizure-free. These findings indicate that rats with focal onset spontaneous seizures respond to the same AEDs as patients with focal onset seizures. Like in humans, the response to AEDs can vary substantially between animals. These observations support the idea that spontaneously seizing animals are a useful tool for testing novel compounds for the treatment of human epilepsy.     

Practical Aspects of Oxcarbazepine Treatment

Summary: In patients with refractory seizures, substitution of oxcarbazepine (OCBZ) for carbamazepine (CBZ) may be associated with reduced seizure frequency and an improved mental state. The recommended dosage of OCBZ as monotherapy for adults with epilepsy is 600-1,200 mg orally per day but may be higher in patients with refractory seizures and in patients requiring combination therapy. When OCBZ is substituted for ongoing CBZ therapy, it is possible to change the dosage immediately so that the patient finishes treatment with CBZ on one day and starts with a full dosage of OCBZ on the next day, even when the full dosage is 50% greater in milligrams than the corresponding CBZ dosage. Allergic skin reactions are rare, and crossreactivity is seen in about 25% of patients hypersensitive to CBZ. Hyponatremia after the use of OCBZ is usually benign, as long as the acute water intoxication is effectively treated. Because of its pharmacokinetic advantages' and efficacy, we believe OCBZ is better than CBZ. We therefore consider OCBZ as the drug of first choice for conditions in which CBZ is currently indicated.     

Felbamate: A Clinical Trial for Complex Partial Seizures

We performed a randomized, double-blind, three-period cross-over study of felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate: Carter-Wallace 554) in patients with complex partial seizures. Patients continued carbamazepine (CBZ) throughout the study and were observed in the hospital for the entire trial period. The entry criteria required at least six seizures in a 3-week baseline period (and no more than 1 week with a single seizure) with CBZ alone. Thirty subjects were randomized. Two left the study after randomization, 1 owing to seizure exacerbation, and 1 owing to hyponatremia, which may have been related to CBZ therapy. The daily dosage of 50 mg/kg (maximum 3,000 mg) FBM per day was well tolerated by all 28 patients who completed the study. Only mild adverse experience were observed during the trial. FBM reduced CBZ level (p less than 0.0001; 95% confidence interval -28%, -20%). There was no significant difference in seizure frequency between placebo and FBM periods (one-sided p = 0.172), but when a correction was made for the lower CBZ level noted during FBM periods, the data suggested a strong antiseizure effect of FBM.     

Exacerbation of partial seizures in a case with heterotopic gray matter using antiepileptic drugs

A two-year-old, right-handed girl was admitted to our hospital with a history of partial seizures. The first seizure, conjugated eye movements and head turning to the right, occurred at the age of 24 months. Later, she suffered from several seizures daily at the age of 34 months. At the age of 35 months, she was admitted to our hospital. On admission her neurological examination was normal. EEG showed a left parietal spike focus. A computed tomographic scan showed a small hyperdense area in the left parietal lobe without contrast enhancement. She was treated with carbamazepine (CBZ : 6 mg/kg/day). When seizures occurred several times within an hour, intravenous or rectal administration of diazepam (DZP : 0.3 mg/kg/dose) was added. However, she complained of sleepiness. The seizures occurred more frequently than before, 50 to 80 times daily, and became secondarily generalized. We thought that the exacerbation of the seizures resulted from the somnolence caused by DZP and CBZ. Consequently, these drugs were discontinued, and phenytoin was begun. She has since been free of seizures for two years. Approximately one year after the discontinuance of DZP and CBZ, heterotopic gray matter and abnormal gyri involving the left parieto-temporal lobe were found by magnetic resonance imaging (MRI). MRI is useful for detecting small heterotopic gray matter. To summarize this case, one should consider the possibility that excessive polytherapy induces seizures, particularly in patients with structural brain abnormalities such as heterotopic gray matter.     

Stimulus-induced focal motor seizure in a pediatric patient with carbamazepine overdose

IntroductionCarbamazepine (CBZ) is a common antiepileptic drug that may cause overdoses with seizures as a common neurological manifestation. In previous reports, patients with CBZ overdose exhibited stimulus-induced generalized clinical or electrical seizures. To date, no previous cases of focal motor seizures have been reported.Case reportWe report the case of an 11-year-old girl with spontaneous and stimulus-induced clustering of focal motor seizures following CBZ overdose. The patient had been treated with CBZ (150 mg daily) for focal epilepsy since the age of six years. At the age of 11, she forgot to take a morning dose, took ten CBZ pills (CBZ 1000 mg) as compensation, and presented with generalized seizures. The patient arrived at the hospital in a coma. She demonstrated clustering of focal-to-bilateral tonic-clonic seizures induced by pain stimulus or spontaneously, with focal epileptiform discharges observed on EEG. Her CBZ blood concentration measured 40.4 μg/mL and she was diagnosed with CBZ overdose. The patient showed improvement without any specific treatment, and was later discharged without neurological sequelae.ConclusionPrevious cases of CBZ overdose with stimulus-induced generalized seizures resulted in death or required intensive care. Stimulus-induced focal seizures may indicate a favorable prognosis for CBZ overdose.     

Brain distribution and efficacy of carbamazepine in kainic acid induced seizure in rats

To investigate the relationships between carbamazepine (CBZ) concentrations in serum and the brain, and the anticonvulsive efficacy in kainic acid (KA) induced seizures in rats, adult Wistar rats (n=25) were intraperitoneally given 40 mg/kg CBZ, followed by 15 mg/kg KA (n=20) or saline (control, n=5). At 90 min after the injection, CBZ concentrations in 5 rats without seizures (CBZ effective group), 5 rats with seizures (CBZ no-effective group) and five control rats were measured. Serum and brain tissues from six areas (cortex, brain stem, cerebellum, thalamus, hippocampus and striatum) were used for CBZ assay. CBZ was measured using a EMIT immunoassay kit. In blood, CBZ was higher in rats treated with CBZ+KA than in a control group (CBZ+saline). In the brain, the effective group demonstrated significantly high CBZ concentration in the hippocampus. KA appeared to raise serum CBZ level when it was given in combination with CBZ. This was probably caused by the accelerated absorption of CBZ from local site as the results of an increased metabolic rate and the more demands for blood supply after KA treatment. The positive correlation between efficacy of CBZ and the concentration in the hippocampus suggests that CBZ levels in the hippocampus is closely correlated with the efficacy of CBZ against KA induced seizures.     

Clinical trials of carbamazepine for autonomic seizures with and without generalized epileptic seizures

Carbamazepine (CBZ) was used for the treatment of 52 children of autonomic seizures with and without generalized epileptic seizures. Their ages ranged from 4 to 17 years. Their autonomic seizures were recurrent episodic headaches and/or abdominal pains. EEG abnormalities were found in all cases in this study. The abnormal EEG findings consisted of diffuse paroxysmal slow dysrhythmia, generalized spike and wave complexes, focal spike and wave complexes with diffuse slow wave bursts, spike and wave complexes with 14 and 6 Hz positive spikes of 14 and 6 Hz positive spikes. Of the 40 patients with autonomic seizures only, 36 (90%) showed disappearance of pain, and of the remaining 4, 2 showed moderate improvement and 2 showed no change as far as their clinical symptoms were concerned. Of the 12 patients with both autonomic seizures and generalized epileptic seizures, 10 (83%) became free from headache and 2 improved moderately. The efficacy of CBZ was found to be very satisfactory. The effective dosage of CBZ ranged from 3.9 to 11.4 mg/kg/day (total dose, 100 to 400 mg/day) with the mean value of 7.0 mg/kg/day.     

Tiagabine in drug-resistant epilepsy in children: preliminary study

The aim of the study was the presentation of our preliminary experiences and the data concerning the efficacy and safety of tiagabine in patients below the 12-th year of life. 4 cases of drug--resistant epilepsy--with partial complex attacks in 3 and simple in 1 (frontal epilepsy from supplementary motor area) with multiple seizures in the day were the subject of the study. Tiagabine add-one therapy to CBZ or to VPA was used. Initial period--the dose titration lasted 4 weeks. The stable dosis period amounted to 5 months. The effective dosis of tiagabine was 1 mg/kg/day. In 1 case the seizures completely disappeared and in 3 the frequency decreased to 2-4 times in comparison to frequency per day before the treatment. There were not any side-effects reported which would be the cause of the drug discontinuation. IN CONCLUSION: Tiagabine appeared to be an effective and safe drug in resistant epilepsy in children below 12 years of age.     

Clinical trial of minimal treatment for clustering seizures in cases of convulsions with mild gastroenteritis

The aim of this study was to identify means of shortening the treatment period for clustering seizures in patients with convulsions with mild gastroenteritis (CwG). Methods: Sixty-two episodes in 61 patients who presented with CwG managed with carbamazepine (CBZ) or Lidocaine (Lidocaine tape (LDT) or intravenous infusion (Lid-iv)) between November 2005 and October 2008 were studied. The subjects were divided into the following groups: 33 episodes treated with CBZ-1 (5 mg/kg/day, 1 day), 7 with CBZ-3 (5 mg/kg/day, 3 days), 11 with LDT-1 (LDT 2 sheets in 24 h), 4 with LDT-2 (LDT 2 sheets in 48 h), and 7 with Lid-iv (1 mg/kg/h, continuous infusion). Results: One to seven seizures were recognized before starting CBZ or Lidocaine therapy, followed by complete cessation in 57 episodes and one or two recurrent seizures in five. Efficacy rates were 97% for CBZ-1, 100% for CBZ-3, 72.7% for LDT-1, 75% for LID-2, and 100% for Lid-iv. Efficacy was significantly higher in the CBZ groups than the Lidocaine groups (p = 0.019), while the differences between treatment periods (CBZ-1 vs. CBZ-3, and Lid-1 vs. Lid-2) did not reach statistical significance (p > 0.999). Conclusions: CBZ and Lidocaine were effective for treating clustering seizures of CwG. We confirmed that the treatment period can be shortened without loss of efficacy. Therefore, we consider 1 day therapy with CBZ or Lidocaine to be sufficient.     

Long-lasting antiepileptic effects of levetiracetam against epileptic seizures in the spontaneously epileptic rat (SER): differentiation of levetiracetam from conventional antiepileptic drugs

PURPOSE: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures. METHODS: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike-wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods. RESULTS: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected 相似文献   

Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep.

OBJECTIVE: To evaluate the cardiac autonomic effects of abrupt withdrawal of carbamazepine (CBZ) during sleep in patients with epilepsy. BACKGROUND: The pathophysiology of sudden unexpected death in epilepsy (SUDEP) is uncertain, with ictal or peri-ictal cardiorespiratory compromise appearing probable. Risk factors for SUDEP include multiple antiepileptic drugs (AED), poor compliance, and abrupt AED withdrawal. The spectral analysis of the beat-to-beat heart rate variability (HRV) displays two main components: low frequency (LF), representing sympathetic and parasympathetic influence and high frequency (HF), representing parasympathetic influence. The LF/HF ratio is commonly regarded as an indicator of sympathovagal balance. METHOD: Twelve patients with medically intractable seizures underwent abrupt withdrawal of CBZ to facilitate seizure recording during controlled circuit TV-EEG monitoring. Continuous EKG recording was begun 24 hours before CBZ reduction. Spectral analysis of the HRV was performed during selected samples of non-REM sleep before and after CBZ reduction. Analyses were made at least 6 hours after from (complex) partial and 12 hours from generalized seizures. RESULTS: The mean LF/HF ratio before withdrawal of CBZ was 2.15 compared with a ratio of 2.65 on day 4 after withdrawal, an increase of 19% (geometric mean; 95% CI, 2% to 34%; Wilcoxon test, z = 2.36; p = 0.018). The ratio increased in 10 patients compared with a decrease in only one patient. CONCLUSION: Abrupt withdrawal of CBZ leads to enhanced sympathetic activity in sleep as evidenced by increased LF/HF ratios. Increased sympathetic activity in the setting of seizure-induced hypoxia could predispose to SUDEP.     

Relationship of Carbamazepine Reduction Rate to Seizure Frequency During Inpatient Telemetry

Summary: To establish guidelines for medication reduction during inpatient telemetry, the records of 18 children and young adults with refractory partial seizures undergoing carbamazepine (CBZ) reductions during continuous video/EEG telemetry were reviewed. Six patients were receiving CBZ monotherapy, and 12 patients were treated with an additional antiepileptic drug (AED) maintained at baseline dosage during CBZ taper. Despite relatively rapid mean reductions in dosage of 44% by day 2 of taper, no patients experienced frequent repetitive seizures or status epilepticus (SE). Seizure rate during the entire CBZ reduction period correlated significantly with rate of drug reduction. Linear regression analysis showed drug reduction rate to be a good predictor of seizure rate. Fourteen patients experienced at least three seizures during CBZ taper. On the average, the third seizure occurred on day 5 of taper at a percentage of dose seduction of 79%. In 8 patients, CBZ concentrations were measured both before taper and ≤24 h after the third seizure. For these patients, seizure rate also correlated significantly with reduction in CBZ level. We conclude that manipulation of CBZ dose reduction rate is important in maximizing seizure frequency during telemetry and, in our patients, a relatively rapid rate of dose reduction was safe and effective in promoting seizure recordings.     

Influence of D-Cycloserine on the Anticonvulsant Activity of Phenytoin and Carbamazepine Against Electroconvulsions in Mice

Summary: Purpose: D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl+-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. Methods: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electro-shock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. Results: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electro-convulsive seizures. DCS in a wide range of doses (1.25–40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. Conclusion: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.     

The influence of gender on the aggravation of absence seizures by carbamazepine in the low-dose pentylenetetrazol rat model.

OBJECTIVES: To determine whether carbamazepine (CBZ) aggravates absence seizures in the low-dose pentylenetetrazol (PTZ) rat model in both male and female animals, and investigate for gender differences. METHODS: Inbred Sprague-Dawley rats were implanted with EEG electrodes. Seven days later PTZ (20 mg/kg, i.p.) was administered following pre-treatment with vehicle or CBZ (20 mg/kg, i.p.) and the occurrence of spike-and-wave discharges (SWDs) on the EEG quantified. RESULTS: The cumulative SWD for 90-minute post-PTZ was higher in the CBZ versus vehicle pre-treatment arm for both female (mean 110 seconds vs. 62 seconds; P = 0.03) and male (mean 89 seconds vs. 60 seconds; P = 0.03) rats. The increase in SWD duration in the CBZ arm was greater in female rats for the first five 15-minute intervals, but none attained statistical significance (P > 0.05). CBZ pre-treatment resulted in reductions in both SWD frequency (Hz) (male, P = 0.003; female, P < 0.0001) and latency to onset of SWD (male, P = 0.002). The frequency of SWD in CBZ pre-treated rats was lower in females (5.8 Hz vs. 6.1 Hz, P = 0.002) as was the decrease in the SWD burst duration following CBZ versus vehicle pre-treatment (-0.05 seconds vs. -0.25 seconds, P = 0.046). CONCLUSIONS: CBZ consistently aggravates absence seizures in the low-dose PTZ model in both female and male rats. However, while some gender differences were found, the results failed to support the hypothesis that females are significantly more susceptible to aggravation of the number or duration of absence seizures by CBZ.     

Epileptic negative myoclonus induced by carbamazepine in a child with BECTS. Benign childhood epilepsy with centrotemporal spikes.

A 7-year-old female with benign childhood epilepsy with centrotemporal spikes developed epileptic negative myoclonus (ENM) seizures during carbamazepine (CBZ) treatment. She had experienced nocturnal partial seizures since 5 years of age. Interictal electroencephalography demonstrated typical rolandic discharges. Valproate was first initiated at 6 years of age, but the seizures were uncontrollable. Carbamazepine was added and valproate withdrawn. The frequency of partial seizures did not decrease. Moreover, she had brief episodes of tone loss in each or both arms and eye blinking several weeks after CBZ introduction. Unilateral loss of arm tone corresponded to spike-and-wave discharges in the contralateral centrotemporal region, and a loss of tone in arms was associated with bilateral synchronous discharges. Eye blinking was also related to bilateral synchronous discharges and classified as a myoclonic seizure. The ENM and myoclonic seizures disappeared soon after CBZ withdrawal. Therefore the authors concluded that CBZ induced the ENM and myoclonic seizures in this patient. CBZ sometimes induces generalized seizures in the treatment of partial epilepsy and generalized epilepsy. CBZ-induced ENM seizures should be considered when a brief lapse of tone appears during CBZ treatment.     

Double-Blind Withdrawal of Phenytoin and Carbamazepine in Patients Treated with Progabide for Partial Seizures

Of 30 patients who completed a study of progabide (PGB) as an add-on to both phenytoin (PHT) and carbamazepine (CBZ), 11 volunteered for a double-blind withdrawal protocol in which the PHT and CBZ were to be withdrawn. All patients were receiving 24-32 mg/kg/day PGB in combination with PHT and CBZ. Each patient was randomly assigned to withdrawal of either CBZ or PHT in the first block, and then withdrawal from the other in the second block in an attempt to achieve PGB monotherapy. Seizure occurrence was monitored by sequential analysis, and if a significant increase over baseline seizure frequency occurred, the dose of PGB was increased to a maximum of 45 mg/kg/day. If seizure frequency remained above baseline, the drug being withdrawn was added back and an attempt made to withdraw the other. The study was terminated if these adjustments were not successful in decreasing seizure frequency to baseline. At the conclusion of the study, three patients were being treated with PGB and PHT, two with CBZ and PGB, and six with all three. This study demonstrated the applicability of sequential analysis to antiepileptic drug trials.     

Comparison of the cognitive effects of tiagabine and carbamazepine as monotherapy in newly diagnosed adult patients with partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies

PURPOSE: Patients with epilepsy are at greater risk for cognitive impairment than are age- and education-matched controls. Cognitive decline is a significant adverse event associated with many first-generation anticonvulsant drugs (AEDs); however, the past decade has seen the introduction of several new AEDs with more-favorable cognitive profiles. Tiagabine (TGB) is indicated as adjunctive therapy for the treatment of partial seizures. The cognitive effects of TGB and carbamazepine (CBZ) monotherapy were evaluated in adult epilepsy patients with partial seizures. METHODS: This analysis pooled data from two randomized studies with similar populations, dosing, and cognitive assessments. TGB was titrated to 20-30 mg/day and CBZ to 400-800 mg/day over a 6-week period. A control or no-drug group of untreated patients with a single epileptic seizure was included for comparison. Cognitive function was assessed at baseline and 52 weeks. RESULTS: Of the 105 epilepsy patients enrolled, 79 completed the 52 weeks of monotherapy (TGB, 74%; CBZ, 77%). Altogether, 19 untreated patients composed the no-drug group. During the 52-week follow-up, only one statistically significant difference was found between the treatment groups and the no-drug group [verbal fluency task: F(2, 92) = 3.16; p = 0.047]. On further analysis, it was determined that this statistical difference was solely based on the patients receiving CBZ performing worse than the control group (p = 0.048). Statistically significant improvements (p < 0.05) were found on six (26%) of 23 variables with TGB and CBZ, as well as the no-drug group, although the variables differed between the groups. Significant worsening in the test scores was not seen in any of the study groups. CONCLUSIONS: The results of this 52-week, follow-up study show that successful TGB monotherapy with 20-30 mg/day has a cognitive profile similar to that of successful long-term CBZ monotherapy with 400-800 mg/day in newly diagnosed patients with epilepsy and to that of untreated patients with a single seizure. We observed no significant decline in cognitive scores associated with TGB monotherapy.     

Carbamazepine dose-concentration relationship in elderly nursing home residents

PURPOSE: To describe the dose-concentration relationships of carbamazepine (CBZ) in elderly nursing home residents and the effect of sex, age, and type of co-medications. RESULTS: This is a cross-sectional study of elderly (> or = 65 years) nursing home residents across the United States (N=92). Data collection was from 1 June 1998 to 31 December 2000. The mean CBZ dose was 9.2+/-5.4 mg/(kg day(-1)) (+/-Standard Deviation) and serum concentration was 5.9+/-2.2mg/L. The daily dose was significantly lower in the oldest-old age group (> or = 85 years, mean 476.9 mg/day (95% confidence interval CI) 326.5-627.3) as compared to the dose in the young-old (65-74 years, mean 724.4 mg/day (CI) 603.4-845.4) (p=0.016). Adjusted for body weight, doses were similar on a mg/(kg day(-1)) basis. The majority of observed CBZ serum concentrations were at the lower end (67.4%) or below (20.7%) the suggested therapeutic range for younger adult outpatients. CONCLUSIONS: Total daily CBZ doses and patient weight decreased with age. The average dose for elderly nursing home residents was approximately 9 mg/(kg day(-1)). Carbamazepine serum concentrations were lower than those used for younger adults, suggesting that these patients may be more sensitive to CBZ.