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.     

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.     

Expanding Antiepileptic Drug Options: Clinical Efficacy of New Therapeutic Agents

Summary: Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM), lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were reviewed. In three European multicenter studies of TPM, the clinical efficacy of 400–, 600–, and 800-mg/day target dosages was demonstrated. In a similarly designed United States trial, LTG was significantly superior to placebo at a 500-mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of smaller trials of VGB suggests that a ≥50% reduction in seizures is observed in approximately 45% of patients with refractory partial epilepsy. All of these newer antiepileptic drugs have shown efficacy in well-controlled trials and should contribute significantly to our ability to manage partial epilepsy.     

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.     

Advances in the Pharmacotherapy of Epilepsy

Summary: Three new antiepileptic drugs (AEDs) are likely to be approved in the United States by the Food and Drug Administration in the near future. In general, all three have good safety profiles, causing only mild, well-tolerated side effects. Felbamate (FBM) is effective in the treatment of partial seizures and Lennox-Gastaut epilepsy. FBM appears to have a broader spectrum of antiepileptic activity than carbama-zepine (CBZ) or phenytoin (PHT). Gabapentin (GBP) was designed to be a structured analogue of γ-aminobutyric acid (GABA). GBP is most effective in the maximal electroshock model of seizures but may have a different mechanism of action than CBZ and PHT. Unique pharmacokinetic properties (no hepatic metabolism and no protein binding) may make GBP especially useful for certain patients, such as those with hepatic disease and elderly patients who are receiving multiple medications. The overall profile of activity of la-motrigine (LTG) is similar to that of PHT and may act on voltage-sensitive sodium channels to stabilize neuronal membranes. LTG is effective in partial seizures, and there is some indication that LTG may be helpful in primary generalized seizures. The long half-life and lack of effect on other AEDs will make LTG easy to dose and add to a patient's existing regimen. These new agents will provide physicians with more effective medications from which to choose in the treatment of the patient with epilepsy.     

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.     

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.     

AUStralian Study of Titration to Effect Profile of Safety (AUS-STEPS): High-Dose Gabapentin (Neurontin) in Partial Seizures

PURPOSE: To evaluate the safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin; GBP) as adjunctive therapy in patients with refractory partial seizures. METHODS: AUS-STEPS was an open-label, multicenter, prospective study in patients experiencing partial seizures who were inadequately controlled with one to three concurrent antiepileptic drugs (AEDs). GBP treatment was titrated to a maximum of 4,800 mg/day, over a treatment period of 24 weeks, to achieve an efficacious and tolerable dosage. Efficacy was assessed by seizure-frequency data. Quality of life was evaluated by using the QOLIE-10 questionnaire, and safety was assessed by adverse-event reports and clinical laboratory findings. RESULTS: A total of 176 patients received treatment with GBP, with 174 evaluable for intention-to-treat (ITT) efficacy analysis. A reduction of >50% in overall seizure frequency was observed in 93 patients (53%). There was a small (4.6%) overall improvement in QOLIE-10 score. The most frequent adverse events were dizziness (31%), fatigue (29%), somnolence (27%), headache (21%), and ataxia (20%), with no major increase seen in adverse events necessitating discontinuation as the dose of GBP was titrated upward. CONCLUSIONS: This study indicates that patients with partial epilepsy may be effectively treated with GBP at dosages of < or =4,800 mg/day, without altering the safety profile of the drug.     

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.     

Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy

PURPOSE: We sought to determine the long-term retention rates of lamotrigine (LTG), gabapentin (GBP), and topiramate (TPM) therapy for patients at a tertiary referral clinic for chronic, refractory epilepsy. METHODS: We analyzed 424 consecutive patients with chronic, refractory partial and/or generalized epilepsy who were started on LTG, 158 patients who were started on GBP, and 393 patients who were started on TPM. The percentages of patients who continued therapy with LTG, GBP, and TPM were estimated with the use of Kaplan-Meier survival analysis. Factors that influence retention were analyzed with the use of Cox regression analysis. RESULTS: Kaplan-Meier survival analysis showed that at 3 years, 30% continued therapy on TPM compared with 29% on LTG and fewer than 10% on GBP. Adverse events resulted in therapy withdrawal in 40% of patients on TPM compared with GBP (37%) and LTG (22%). Perceived lack of efficacy led to treatment withdrawal in 39% of patients on GBP compared with 34% on LTG and 19% on TPM. Cox regression estimated that a fourth or fewer of patients with chronic partial epilepsy are likely to continue therapy with a new antiepileptic drug beyond 5 years. CONCLUSIONS: The impact of these new antiepileptic drugs on the long-term course of chronic partial epilepsy is likely to be small, as approximately three of four patients will discontinue therapy. More patients appear to continue on TPM compared with LTG or GBP, with a possible reason being better perceived efficacy of TPM, despite having the highest incidence of adverse events.     

Efficacy of Topiramate as Adjunctive Therapy in Refractory Partial Seizures: United States Trial Experience

Summary: In companion double-blind, placebo-controlled, dose-ranging trials performed in the United States, topiramate (TPM) daily target dosages of 200-1,000 mg/day were evaluated as add-on therapy in adults with refractory partial seizures with or without becoming secondarily generalized. Net reductions in median monthly seizure frequency (active drug minus placebo) with the most efficacious dosages of TPM were 35% in the low-dose trial and 40% in the high-dose trial. Substantial reductions in secondarily generalized seizures were also observed with TPM. TPM appears to be an efficacious new antiepileptic drug in the management of partial epilepsy.     

Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

Felbamate in the Treatment of Partial-Onset Seizures

Summary: Felbamate (FBM, Felbatol/Taloxa) has been the object of several trials that are innovative and unique. First, FBM is the first antiepileptic drug (AED) to have been submitted to a controlled efficacy study in patients with the Len-nox-Gastaut syndrome (LGS) before being submitted for regulatory approval. Second, FBM was tested in patients discontinued from other AEDs for presurgical monitoring. Third, FBM was the first experimental AED to have been tested in controlled monotherapy trials. Overall, these studies succeeded in demonstrating that FBM is relatively safe and effective against both partial-onset seizures and the generalized seizures occurring in the LGS. The results of some of these studies could not always be expressed by using the more familiar concept of percent seizure reduction because, for ethical reasons, the efficacy variable had to be defined in terms of time to the n^lh seizure or in terms of escape criteria. This may make it more difficult to evaluate just how effective FBM is in comparison with other AEDs. Another reason why the efficacy of FBM cannot yet be fully assessed is that in all the studies the FBM dosage was limited to a maximum of 3,600 mg/day or 45 mg/kg/day. At this dosage, FBM produced no toxicity in the majority of patients, and its full therapeutic effect may have to be re-evaluated in the future at higher dosages.     

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.     

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.     

Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients

A retrospective analysis of charts of patients who received gabapentin (GBP) as adjunctive anticonvulsant therapy in its first year of marketing, between March 1994 and April 1995 was conducted to evaluate patterns of use, side effects, and efficacy in the general epilepsy population. Ninety patients (45 men, 45 women) with an average age of 33.5 years (range: 7 months–78 years) were included. Average GBP dosage was 1700 mg/day; 46 patients took <1800 mg, and 44 patients took ⩾1800 mg/day. Duration of GBP treatment ranged from 1 month–14 months. Patients took an average of 1.7 concurrent antiepileptic drugs while on GBP. A total of 13 patients were on GBP monotherapy, four at the outset joined by nine others during the study. Gabapentin was associated with improvement as assessed by reduction of seizure frequency in 69 patients (77%). Sixty patients (67%) who reported no side effects had a mean GBP dosage of 1900 mg/day (median: 2000 mg/day). The 30 patients who experienced side effects had a mean GBP dosage of 1600 mg/day (median: 1500 mg/day). Gabapentin was discontinued in 21 patients, six because of side effects, nine because of lack of efficacy, and six because of a combination of both. Gabapentin was used in more difficult patients with intractable epilepsy and was generally well tolerated. Higher doses were not associated with more side effects, suggesting that GBP-related side effects may not be dose-related.     

妥泰加用治疗成人难治性部分性癫痫的疗效观察

目的：观察妥泰（TPM）加用治疗成人难治性部分性伴或不伴随继发身性发作（GTCS）的疗效,安全性及耐受性。方法：56例在不动原用抗癫痫药（AEDs)的基础上加用TPM治疗20周、前8周为加量期,后12周为维持治疗的稳定期,治疗前（基础期）记录好作频率,用药情况。体重等作为自身对照。TPM自25mg/d开始,逐渐加量,目标剂量为200mg/d,治疗及治疗结束各查基础AEDs血药浓度进行比较,治疗结束行全面疗效分析。结果：TPM加用治疗20周后,与基础期发作频率比较,64．29％患者发作频率降低≥50％;25．00％,患者发生频率降低≥75％＜100％;16．07％完全不发。不良反应轻至中度,但与合AEDs的多少有关。50％患者体重可有不同程度的下降。TPM对止痛民西平及丙戊酸钠血药浓度影响不大。结论：TMP是治疗难治性部分性伴或不伴继发GTCS的表效的药物。     

A pooled analysis of adjunctive topiramate in refractory partial epilepsy

OBJECTIVES: To evaluate the impact of different dosages of topiramate (TPM) add-on to stable antiepileptic therapy for refractory partial epilepsy in adults. MATERIAL AND METHODS: Pooled intention-to-treat analysis of six similarly designed double-blind, placebo-controlled trials, including 481 patients treated with doses of TPM 200, 400, 600 and 800 mg/day, and 265 patients receiving placebo. RESULTS: Seizures were reduced by >/=50% from baseline in 41% of TPM-treated patients and 15% of placebo-treated patients (P < 0.001); 5 and 0.8%, respectively, were seizure-free (P < 0.003). TPM was significantly better than placebo regardless of gender, age, baseline seizure rate as well as number and type of concomitant antiepileptic drugs. Efficacy was statistically significant in favour of TPM at all dose levels: at least 50% seizure reduction was achieved in 40% of patients with 200 mg, 41% with 400 mg, 44% with 600 mg and 41% with 800 mg TPM when compared with 15% with placebo (P 相似文献