Pharmacokinetics and Interaction Profile of Topiramate: Review and Comparison with Other Newer Antiepileptic Drugs

Summary: Standard antiepileptic drugs (AEDs) have a number of pharmacokinetic shortcomings, and AEDs with more favorable profiles would be preferred. The pharmacokinetics and interaction profile of the recently developed AED topiramate (TPM), is reviewed and compared with those of other newer AEDs including lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB), and oxcarbazepine (OCBZ). Although none of these agents meets all of the criteria of the "ideal" AED from the pharmacokinetic standpoint, a number of these drugs, including TPM, have desirable properties that distinguish them from the older AEDs and should contribute to their clinical utility.     

The New Antiepileptic Drugs and Women: Efficacy, Reproductive Health, Pregnancy, and Fetal Outcome

Summary: As new antiepileptic drugs (AEDs) become available, physicians will define their appropriate use in particular patient populations. For women, the issues in clude gender-specific efficacy and tolerability, including the impact of the AED on reproductive health. Women with epilepsy who are treated with established AEDs ap pear to be at risk for compromised bone health, for dis turbances in fertility, menstrual cyclicity, ovulatory func tion, and sexuality and, with some AEDs, for failure of hormonal contraception. Finally, pregnancy outcome may be adversely affected by the established AEDs, all of which are human teratogens. Felbamate (FBM), gabap-entin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were reviewed. The preclinical development pro cess had not addressed all the issues of concern to women. Although gender-specific efficacy is routinely evaluated, impact on reproductive health is not. FBM, GBP, LTG, TGB, TPM, and VGB have similar efficacy in women and men. It is not known whether the new AEDs will affect bone health, fertility, the menstrual cycle, and sexuality. FBM, GBP, LTG, TGB, and probably VGB do not interfere with hormonal contraception. Whether these new AEDs are good choices for the pregnant woman with epilepsy awaits further experience in human pregnancy. However, animal reproductive toxicology studies appear promising. The limited number of human pregnancy ex posures do not, thus far, signal a significant number or particular type of adverse outcomes. However, only with improved postmarketing surveillance can essential infor mation about teratogenic effects be acquired in an accept ably short time.     

Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.     

Interaction between anticonvulsants and human placental carnitine transporter

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.     

Overview of the Safety of Newer Antiepileptic Drugs

Summary: Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.     

Antiepileptic Drug Mechanisms of Action

Summary: Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, γ-ami-nobutyric acid type A (GABA_A) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABA_A receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underlie the clinical efficacy of VGB.     

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Vigabatrin,but not gabapentin or topiramate,produces concentration-related effects on enzymes and intermediates of the GABA shunt in rat brain and retina

PURPOSE: The antiepileptic drug (AED) vigabatrin (VGB), which exerts its pharmacologic effects on the gamma-aminobutyric acid (GABA) system, causes concentric visual field constriction in >40% of exposed adults. This may be a class effect of all agents with GABA-related mechanisms of action. We compared the concentration-related effects of VGB in rat brain and eye with those of gabapentin (GBP) and topiramate (TPM), both of which have been reported to elevate brain GABA concentrations in humans. METHODS: Adult male rats (n = 10) were administered 0.9% saline (control), VGB (250, 500, 1,000 mg/kg), GBP (50, 100, 200 mg/kg), or TPM (12.5, 25, 50, 100 mg/kg). At 2 h after dosing, animals were killed, a blood sample obtained, the brain dissected into eight distinct regions, and the retina and vitreous humor isolated from each eye. Samples were analyzed for several GABA-related neurochemical parameters, and serum and tissue drug concentrations determined. RESULTS: VGB treatment produced a significant (p < 0.05) dose-related increase in GABA concentrations and decrease in GABA-transaminase activity in all tissues investigated. This effect was most pronounced in the retina, where VGB concentrations were 18.5-fold higher than those in brain. In contrast, GBP and TPM were without effect on any of the neurochemical parameters investigated and did not accumulate appreciably in the retina. CONCLUSIONS: These findings corroborate a previously reported accumulation of VGB in the retina, which may be responsible for the visual field constriction observed clinically. This phenomenon does not appear to extend to other GABAergic drugs, suggesting that these agents might not cause visual field defects.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

Clobazam, Oxcarbazepine, Tiagabine, Topiramate, and Other New Antiepileptic Drugs

Summary: Clinical investigators recently have studied at least 21 new antiepileptic drugs (AEDs) in people with epilepsy. This review briefly examines 15 of these new AEDs: clobazam (CLB), dezinamide, flunarizine (FNR), loreclezole, milacemide (MLM), MK-801, nafimidone, ORG-6370, oxcarbazepine (OCBZ), progabide (PGB), ralitoline, stiripentol, tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS). CLB, PGB, and TGB represent agents that act on the GABA system, and MLM acts on the glycine system. MK-801 and ZNS (in part) are excitatory amino acid antagonists, and FNR is a calcium-channel antagonist. OCBZ is a keto analogue of carbam-azepine, which is not metabolized to the epoxide and may have fewer side effects. The remaining agents are novel compounds with a variety of suspected mechanisms. TPM appears especially effective for intractable partial seizures but has a high incidence of cognitive side effects. None of these new AEDs is useful for all patients with inadequate seizure control or ongoing toxicity. The role of each will require further clinical study and experience.     

Sildenafil influences the anticonvulsant activity of vigabatrin and gabapentin in the timed pentylenetetrazole infusion test in mice

Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to affect convulsant activity in some animal models of seizures and epilepsy. Moreover, its influence on the protective activity of some antiepileptic drugs (AEDs) was also noted. The aim of the present study was to investigate the effect of sildenafil on the anticonvulsant potential of gabapentin (GBP) and vigabatrin (VGB) in the timed intravenous (i.v.) pentylenetetrazole (PTZ) test in mice. The chimney test, the passive avoidance task and the grip strength test were used to estimate some possible side effects caused by the studied AEDs and their combinations with sildenafil. Total brain and free plasma concentrations of GBP and VGB were determined to evaluate the characteristics of interactions. Our studies revealed that GBP (25-100mg/kg) increases the threshold for the forelimb tonic extension, whereas VGB raises thresholds both, for myoclonic (200-600mg/kg) and generalized clonic (400-600mg/kg) seizures in the used model of seizures. GBP at sub-effective dose of 12.5mg/kg co-administered with sildenafil at doses of 10 and 20mg/kg significantly increases the threshold for tonic seizures in the i.v. PTZ test in mice. Combination of sub-effective dose of VGB (200mg/kg) with sildenafil at a dose of 5mg/kg also showed significant anticonvulsant activity against clonic seizures. The studied AEDs and their combinations with sildenafil did not produce any changes in the motor coordination, long-term memory and muscular strength in mice. Sildenafil did not influence total brain and free plasma concentrations of GBP and VGB. Interactions between the studied AEDs and sildenafil were pharmacodynamic in nature and for that reason they are worthy of consideration in the clinical practice.     

The Long-Term Use of Gabapentin, Lamotrigine, and Vigabatrin in Patients with Chronic Epilepsy

PURPOSE: To compare the long-term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure-related injury/hospital admission and mortality after these drugs were commenced. METHODS: This was a retrospective case-records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan-Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure-related injury/hospital admissions and standardised mortality ratios were calculated. RESULTS: There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was <40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure-related injury/admission. CONCLUSIONS: The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.     

The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.

PURPOSE: Lamotrigine (LTG), vigabatrin (VGB) and gabapentin (GBP) are three anti-epileptic drugs (AEDs) used in the treatment of children with epilepsy for which long-term retention rates are not currently well known. This study examines the efficacy, long-term survival and adverse event profile of these three agents used as add-on therapy in children with refractory epilepsy over a 10-year period. METHODS: Three separate audits were conducted between February 1996 and September 2000. All children studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure free or achieved >50% reduction in seizure frequency for 6 months or more after starting therapy. Adverse events and patient survival for each drug were recorded at the end of the study period. RESULTS: Between September 1990 and February 1996, 132 children received LTG, 80 VGB and 39 GBP. At the 10-year follow-up audit, 33% of the children on LTG had a sustained beneficial effect on their seizure frequency in contrast to 19% for VGB and 15% for GBP. No significant difference in efficacy was found in children with partial seizures. Children with epileptic encephalopathy (EE) including myoclonic-astatic epilepsy and Lennox-Gastaut Syndrome (LGS) achieved a more favorable response to LTG. The main reasons for drug withdrawal were lack of efficacy for VGB, apparent worsening of seizures for GBP and the development of a rash for LTG. CONCLUSIONS: Lamotrigine is a useful add-on therapy in treating children with epilepsy. It has a low adverse event profile and a sustained beneficial effect in children with intractable epilepsy.     

Clinical science

Ognen A. C. Petroff , Fahmeed Hyder , Douglas L. Rothman , and Richard H. Mattson
Yale researchers in pioneering work have been able to study the effects of antiepileptic drugs (AEDs) on the brain chemistry of people with epilepsy in a safe and painless manner by using the principles of magnetic resonance imaging (MRI). Neurons in the human brain make homocarnosine from γ-aminobutyric acid (GABA; the brain's main inhibitory neurotransmitter) and histidine in larger amounts than the neurons of almost all other animals. Three of the newer AEDs, gabapentin (GBP; Neurontin), topiramate (TPM; Topamax), and vigabatrin (Sabril), increase human homocarnosine levels. We measured homocarnosine and GABA levels of 20 patients with complex partial seizures taking GBP and 17 patients taking TPM. Homocarnosine levels were higher in patients with better seizure control than in those whose seizure control was below the middle value (median) for the two groups. No differences were found in the GABA levels between the patients, who showed a better response to GBP or TPM, compared with those who did not. Higher homocarnosine levels (above the median) were associated with better seizure control in the patients taking GBP or TPM; higher brain GABA levels appeared to offer no additional protection. The current results are similar to our previously published findings, which showed higher brain homocarnosine levels in patients with juvenile myoclonic epilepsy with excellent seizure control, taking valproate (Depakote) or lamotrigine (Lamictal), than the levels of patients with more frequent seizures. The data support the hypothesis that increased homocarnosine and GABA levels contribute to the anticonvulsant properties of GBP and TPM, perhaps by limiting the spread of seizures from the areas where seizures start.     

Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability

We compared the long-term retention rates of several newly licensed antiepileptic drugs (AEDs) in a residential community of adults with chronic epilepsy and learning disability. Data relating to duration of therapy, maximum dose, and tolerability of six new AEDs-gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TIA), and topiramate (TPM)-were collected. Drug retention at 2 years was 85% (OXC), 57% (LTG), 56% (LEV), 45% (TPM), 24% (TIA) and 15% (GBP). OXC was used mainly as a substitute for carbamazepine. LTG, LEV, and TPM were all associated with retention rates higher than those of GBP or TIA. TPM had the highest rate of adverse event development at the maximum tried dose (60%), whereas LEV had the lowest (16%). Experience from this single epilepsy community study indicated limited impact for GBP or TIA but higher retention of OXC, LEV, LTG, and TPM in patients with chronic epilepsy and learning disability.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

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.     

An In Vitro Study of New Antiepileptic Drugs and Astrocytes

Summary:  Purpose: The aim of our research was to study some biochemical modifications elicited in primary rat astrocyte cultures by treatment with gabapentin (GBP), carbamazepine (CBZ), lamotrigine (LTG), topiramate (TPM), oxcarbazepine (OXC), tiagabine (TGB), and levetiracetam (LEV), commonly used in the treatment of epilepsy. We investigated the biologic effects of these anticonvulsants (AEDs) at concentrations of 1, 10, 50, and 100 μg/ml.
Methods: The study was performed by examining cell viability (MTT assay), cell toxicity [lactate dehydrogenase (LDH) release in the medium], glutamine synthetase (GS) activity, reactive oxygen species (ROS) production, lipoperoxidation level (malondialdehyde; MDA), and DNA fragmentation (COMET assay). The level of the expression of 70-kDa heat-shock protein (HSP70) and inducible nitric oxide synthase (iNOS) as oxidative stress–modulated genes also was determined.
Results: Our experiments indicate that CBZ, TPM, and OXC induce stress on astrocytes at all concentrations. GBP, LTG, TGB, and LEV, at low concentrations, do not significantly change the metabolic activities examined and do not demonstrate toxic actions on astrocytes. They do so at higher concentrations.
Conclusions: Most AEDs have effects on glial cells and, when used at an appropriate cell-specific concentrations, may be well tolerated by cortical astrocytes. However, at higher concentrations, GBP, LTG, TGB, and LEV seem to be better tolerated than are CBZ, TPM, and OXC. These findings may reveal novel ways of producing large numbers of new AEDs capable of reducing the extent of inflammation, neuronal damage, and death under pathological conditions such as epilepsy and/or traumatic brain injury.