Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study

PURPOSE: To evaluate pregabalin as add-on therapy for patients with partial seizures administered as fixed dose or as flexible dose adjusted to optimal seizure reduction and tolerability. METHODS: Patients receiving antiepileptic drugs (98.8% between 1 and 3 AEDs; 1.2% on more than 3 AEDs) and experiencing > or =4 partial seizures during the 6-week baseline period and no 4-week seizure-free interval were randomized (1:2:2) to placebo (n = 73), pregabalin fixed dose (600 mg/day BID; n = 137), or pregabalin flexible dose (n = 131; 150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each, BID) for 12 weeks. Dosage could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved. Primary efficacy parameter was reduction in seizure frequency from baseline. RESULTS: Both pregabalin regimens significantly reduced seizure frequency compared with placebo, by 35.4%, for flexible dose (p = 0.0091) and 49.3% for fixed dose (p = 0.0001) versus 10.6% for placebo, and the fixed-dose group was superior to the flexible-dose group (p = 0.0337). Most adverse events were mild or moderate. Discontinuation rates due to adverse events were 6.8% (placebo), 12.2% (pregabalin flexible dose), and 32.8% (pregabalin fixed dose). Patients receiving pregabalin fixed dose discontinued due to adverse event earlier than other groups. CONCLUSIONS: Pregabalin administered twice daily, either as fixed (600 mg/day), or as flexible (150-600 mg/day) dose, was highly effective and generally well-tolerated as add-on therapy for partial seizures with or without secondary generalization. Lower incidence of adverse events and discontinuations were achieved in patients receiving pregabalin when dosing was individualized to optimize efficacy and tolerability.     

The impact of background antiepileptic drugs on the efficacy and safety of pregabalin in treating partial-onset seizures: a post hoc analysis of combined clinical trials

Pregabalin is used as adjunctive treatment for partial-onset seizures and is often combined with multiple antiepileptic drugs (AEDs) from different classes. The objectives of this post hoc analysis were to evaluate the efficacy and safety of pregabalin when added to different AED regimens and to identify specific AED combinations that in conjunction with pregabalin yield high responder rates. Data from six double-blind, randomized studies of pregabalin in patients with partial-onset seizures were pooled for analysis (N=1775). When the treatment groups (placebo, 150mg, 300mg, 600mg, and flexible dose) were stratified by the number of concomitant AEDs (one, two or three or more), modeling results suggested that the magnitude of improvement on either ≥50% responder rate or mean response ratio remained consistent regardless of the number of concomitant AEDs. Adverse events were typical of pregabalin and, in general, did not vary as the number of concomitant AEDs increased. A cluster analysis was performed to identify possible combinations of AEDs that yielded high ≥50% responder rates. The majority of patients (>90%) fell within two clusters that yielded high responder rates, while <10% of the patients fell within two clusters that yielded low responder rates. Numerous AED combinations, ranging from 6 to 11, occurred within each cluster. In summary, pregabalin provided a consistent improvement in seizure reduction and comparable tolerability in patients with partial-onset epilepsy regardless of the number of concomitant AEDs.     

Defining success in clinical trials – profiling pregabalin, the newest AED

The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials ( n  = 1396) and four long-term open-label studies ( n  = 1480). Patients in the three fixed-dose trials were ≥12 years of age, had ≥6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking ≥2 concomitant antiepileptic drugs. Responder rates across the effective doses (150–600 mg/day) ranged from 14% to 51% and demonstrated a significant dose–response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150–600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P  < 0.001) and flexible dose (31.3%, P  < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated.     

Pregabalin As Adjunctive Therapy for Partial Seizures

Summary:  The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been studied in three randomized, double-blind, placebo-controlled trials involving 1,052 patients. Patients (≥12 years of age) participating in the trials were highly refractory to treatment, experiencing at least six seizures and no 4-week seizure-free period during the 8-week baseline phase, even though 73% received at least two antiepileptic drugs and 23% received three. Each fixed-dose study was 12 weeks in duration. In Study 1, patients received pregabalin 50, 150, 300, or 600 mg/day given two times daily with no titration period. Studies 2 and 3 had a 1-week titration to dose levels of 150 and 600 mg/day given three times daily (Study 2), 600 mg/day given two times daily, and 600 mg/day given three times daily (Study 3). Pregabalin, at 150, 300, and 600 mg/day, was significantly superior to placebo in reducing seizure frequency with a clear dose–response relationship. Responder rates, defined as the percentage of patients with ≥50% reduction in seizure frequency from baseline, approached 50% at 600 mg/day. In the effective dose range (150–600 mg/day), seizure freedom in the last 28 days of treatment was 3–17%. There was no difference between two times daily and three times daily dosing regimens. Efficacy was apparent as early as week one. The most commonly reported adverse events were CNS related, and either mild or moderate in intensity and generally self limiting. Few patients (≤5% in any treatment group) discontinued due to lack of efficacy. These results indicate that pregabalin is highly effective as adjunctive therapy in the treatment of patients with partial seizures with or without secondary generalization.     

Pregabalin for the management of partial epilepsy

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a ≥50% reduction in seizure frequency across the effective dose-range (150–600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy.     

Pregabalin: a new antiepileptic drug for refractory epilepsy.

Pregabalin is a recently licensed and marketed antiepileptic drug for use as adjunctive treatment of partial epilepsy. It acts at presynaptic calcium channels, modulating neurotransmitter release in the CNS, properties it shares with gabapentin. Its clinical development over the past decade has included its use in the treatment of neuropathic pain, and generalized anxiety disorder, in addition to epilepsy. Three multi-centre randomised, double-blind, placebo-controlled trials enrolling patients with refractory partial epilepsy have demonstrated an antiepileptic effect of pregabalin against placebo, as adjunctive therapy, with 31-51% of patients showing a 50% reduction in seizure frequency. Adverse effects were dose related, the commonest being somnolence, dizziness, and ataxia. Weight gain was seen in 14% of patients on the highest dose of 600 mg/day. Around 9000 people have been exposed to pregabalin in its development for all indications. No idiosyncratic reactions have been described to date. Pregabalin may be a useful addition in the treatment of refractory partial epilepsy. As with all new AEDs long-term follow up and post marketing surveillance is required.     

Lamotrigine High-Dose Tolerability and Safety in Patients with Epilepsy: A Double-Blind, Placebo-Controlled, Eleven-Week Study

Summary: Purpose: This study was undertaken to evaluate the dose tolerability and safety of a chronic ascending twice-daily (b.i.d.) dosage regimen of 700 mg/day larnotrigine (LTG) and to include determination of the LTG pharmacokinetic profile at doses 500 mg/day in patients receiving concomitant enzyme-inducing antiepileptic drugs (AEDs). Methods: Twelve adult male epileptic patients treated with enzyme-inducing AEDs received 700 mg/day (b.i.d.) oral LTG (n = 8) or placebo (controls, n = 4). For 3 weeks, as outpatients they had their LTG dosage increased from 100 to 400 mg/day. Then, in a clinical research study unit, patients received regimens of 500, 600, and 700 mg/day for 1 week each. Controls received matching placebo in the same sequence. At study end, dosages were tapered in 2 weeks. Follow-up evaluations were made 7 days later. Results: Five LTG patients tolerated 700 mg/day for 1 week. LTG was reduced to 600 mg/day in a patient with mild diplopia and to 500 mg/day in a patient with mild oscillopsia and diplopia. One patient discontinued 300-mg/day therapy with a moderately intense diffuse papular skin rash, attributed to LTG. Headache, drowsiness, faintness, and diplopia, the common adverse events (AEs), were mild to moderate in intensity and occurred in 50–75% of patients in both groups (except for diplopia, occurring only with LTG). Concomitant AED plasma concentrations were not markedly changed by LTG. LTG pharmacokinetics were linear over the range of 500–700 mg/day. Conclusions: LTG doses 700 mg/day can be tolerated in patients receiving concomitant enzyme-inducing AEDs.     

Long‐term add‐on pregabalin treatment in patients with partial‐onset epilepsy: Pooled analysis of open‐label clinical trials

Purpose: To evaluate the safety, tolerability, and efficacy of long‐term pregabalin as add‐on therapy for patients with poorly controlled partial seizures. Methods: Analysis of data from six long‐term clinical trials involving 2,061 patients receiving open‐label pregabalin 75–600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs. Results: Total pregabalin exposure was 3,877 person‐years. The mean duration of pregabalin treatment was 534 days (range 0.3–8 years) and 59% completed 1 year. One‐third of patients discontinued for lack of efficacy. The most common dose was ≥300 mg/day; over half took ≥450 mg/day. There was a mean reduction in the 28‐day seizure rate of 25–40%, and more than 40% of all patients had a ≥50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6‐month period continuously free of seizures. In the last year, 6% were seizure‐free for the entire year. Pregabalin was generally well‐tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short‐term placebo‐controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population. Conclusions: Adjunctive pregabalin was effective, generally well tolerated, and safe in the long‐term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow‐up.     

Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures

PURPOSE: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. METHODS: During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. RESULTS: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p=0.0038) and 600 mg/day (p=0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. CONCLUSIONS: In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.     

Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial

Purpose: To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs). Methods: This multicenter, double‐blind, placebo‐controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8‐week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force‐titrated weekly (100 mg/day increments) to the target dose, and entered a 12‐week maintenance period. Results: A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention‐to‐treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic–clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose‐related adverse events included dizziness, nausea, and vomiting. Discussion: Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial‐onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic–clonic seizures.     

Stiripentol in Atypical Absence Seizures in Children: An Open Trial

Summary: Stiripentol (STP) was added to the antiepileptic drug (AED) regimen of 10 patients with uncontrolled atypical absence seizures (more than one seizure a day). Seven boys and three girls aged 6–16 years participated in the study. Concomitant AEDs included various combinations of phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA). Parents counted daily seizures over a 4-week baseline period before institution of STP, and in a 20-week period during STP therapy. To compensate for drug interactions, doses of other AEDs were adjusted during STP administration to keep serum levels close to levels of the baseline period. Maintenance doses of STP were 1,000–3,000 mg/day, giving serum levels of 4–22 μg/mL. All patients experienced a decrease in atypical absence seizures. Average decrease was 70% (range 5–95%). Side effects experienced by some patients were dose related and included anorexia, nausea, vomiting, and lethargy. In only 1 patient did an adverse effect (vomiting) require discontinuation of STP. We conclude that STP shows promise in treatment of atypical absence seizures in children, and further trials are warranted.     

固定剂量法和滴定法给予普瑞巴林治疗中枢性卒中后疼痛的疗效比较

目的比较固定剂量法和滴定法给予普瑞巴林治疗中枢性卒中后疼痛的疗效。方法采取连续入组方式筛选入组厦门大学附属第一医院中枢性卒中后疼痛的患者,随机分为固定剂量法组和滴定法组。固定剂量法组给予普瑞巴林300 mg/d,连续服用8周;滴定法组给予普瑞巴林150 mg/d×2周,300 mg/d×2周,450 mg/d×4周。以数字评价量表(NRS)作为主要终点指标,以药物不良反应、医院焦虑抑郁量表(HADS)评分和睡眠自测量表(AIS)评分作为次要终点指标。结果 2013年7月~2014年12月在本院神经科和疼痛科筛选入组共计132例患者,随机分给固定剂量法组65例,滴定法组67例。两组因药物不良反应或难以坚持服药等原因分别退出2例、7例患者。固定剂量法组和滴定法组最终纳入统计的例数分别是63例和60例,两组间性别、年龄、病史、用药史等基础资料的比较差异均无统计学意义。与治疗前比较,固定剂量法组和滴定法组治疗后NRS评分、HADS-A评分、HADS-D评分及AIS评分均显著降低(均P0.05)。两组间治疗后NRS评分、HADS-A评分、HADS-D评分及AIS评分的比较,差异无统计学意义。结论固定剂量法和滴定法给予普瑞巴林治疗CPSP患者都是安全有效的,而固定剂量法的患者依从性似乎更高。     

托吡酯单用及添加治疗癫痫302例临床分析

目的　观察托吡酯添加和单药治疗癫痫的临床疗效及不良反应 ,并探讨单药治疗的理想给药模式。方法　入组患者分为 3组 ,A组 10 2例采用托吡酯添加治疗 ,B组 2 0 0例采用托吡酯单药治疗 ,按初始剂量及加量速度不同 B组又分为 B1组、B2组。B1组 10 5例 ,妥泰初始剂量 2 5 mg/ d,增量 2 5 m g/ w至 2 0 0 m g/ d;B2组 95例 ,妥泰初始剂量 5 0 mg/ d,增量 5 0 m g/ w至 2 0 0 m g/ d。维持治疗 12周。记录发作情况及不良反应。结果　 A组总有效率及控制率分别为 6 0 .8%、2 4 .5 % ,B组总有效率及控制率为 76 .8%、4 1.5 % ,两组疗效差异有显著性意义 (P<0 .0 5 )。 B1组总有效率及控制率分别为 77.9%、4 1.9% ,B2组总有效率及控制率分别为 75 .8%、4 0 .0 % ,两组疗效差异无显著性意义 (P>0 .0 5 )。托吡酯对各型部分性发作及强直 -阵挛性发作的疗效差异无显著性意义 (P>0 .0 5 )。B2组不良反应高于 B1组 ,差异有显著性意义 (P<0 .0 5 )。结论　托吡酯添加及单药治疗癫痫具有良好的疗效 ,对发作频率较低的患者宜选用小剂量起始缓慢加量的治疗方法 ,对发作频率较高的患者可考虑予较大起始剂量并以较快速度加量以尽快控制发作     

Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.

The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.     

Add-on treatment with pregabalin for partial seizures with or without generalisation: Pooled data analysis of four randomised placebo-controlled trials

Pooled data analysis was performed on individual data from 807 pregabalin- and 367 placebo-treated patients with treatment-resistant partial seizures with or without generalization from four placebo-controlled studies evaluating the short-term efficacy, safety and tolerability of add-on pregabalin 150–600 mg/day. Short-term add-on treatment with pregabalin resulted in statistically significant reductions from baseline in seizure frequency and statistically significantly higher responder rates over placebo (OR 5.93 [95% CI 4.10, 8.57]). Its overall tolerability was good, with an OR of withdrawing from the study due to any reason of 1.71 (95% CIs 1.24, 2.35). The most commonly reported AEs were dizziness and somnolence, however, they were most pronounced during the first week of treatment, followed by a sharp fall in incidences across all dosing groups to <5% from Week 2 and onwards. Weight gain, reported by 5.4–17.1% of patients across pregabalin dosing groups, appeared to be dose-related, but it led to study withdrawal in only 0.74% (6 out of 810) pregabalin-treated subjects. Our analysis suggests that pregabalin has a robust efficacy and good tolerability demonstrated in a study population more treatment-refractory compared to the one enrolled into short-term studies of other new antiepileptic drugs.     

Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures

Summary: Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add‐on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). Methods: An international (13 countries), multicenter (45 centers), 12‐week, double‐blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8‐week baseline (pretreatment phase) and the 12‐week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent‐to‐treat population. Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [–11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure‐frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose‐related, treatment‐emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well‐tolerated add‐on therapy in patients with partial seizures.     

Assessing the unmet treatment need in partial-onset epilepsy: looking beyond seizure control

Patients with resistant epilepsy are often coprescribed multiple medications and are more likely to experience drug-drug interactions and adverse events (AEs). A new generation of antiepileptic drugs (AEDs) has been developed with improved safety/tolerability profiles. To evaluate the unmet treatment needs in epilepsy, a comprehensive search of the English-language literature was conducted on Medline and other databases using the terms "partial epilepsy" and "focal seizure," focusing on newer AEDs. Sixty-nine articles were identified. Most patients experienced AEs, which were generally mild-moderate in severity. Drug-drug interactions existed for 6 of 11 AEDs for which data were available. There is evidence for depressive symptoms being associated with zonisamide, and mood-stabilizing effects were shown for lamotrigine and pregabalin. Levetiracetam and eslicarbazepine improved cognitive function. Vigabatrin may increase the risk of developing psychosis. Health-related quality of life (HRQoL) was inversely correlated with seizure frequency. Discontinuation rates were often high, although treatment retention improved with slower dose titration. Adjunctive therapy with newer AEDs has the potential to enhance HRQoL and treatment continuation in patients with partial epilepsy. There remains room for improvement in the management of epilepsy, and better treatments and longer-term trials are needed to meet the special requirements of refractory patients.     

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001).The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.     

Adjunctive pregabalin therapy in mentally retarded, developmentally delayed patients with epilepsy

This retrospective study evaluated the efficacy and tolerability of adjunctive pregabalin (PGB) therapy in mentally retarded, developmentally delayed patients. The primary efficacy measure was the change in the median frequency of seizure days per week between the baseline (8 weeks prior to initiating PGB) and treatment (12 weeks of titration and maintenance) periods. Inclusion criteria were: documented epilepsy treated with antiepileptic drug, at least one seizure during the baseline period, and lack of prior exposure to PGB. Seven patients (four female, three male, mean age=43) with multiple seizure types (generalized tonic-clonic, tonic, partial, and atypical absence) met the inclusion criteria. The mean dose of PGB was 293 mg/day (range=150-350 mg/day). PGB was efficacious, resulting in a significant reduction in the median frequency of seizure days/week between baseline and treatment (1.38 vs 0.50, P=0.018). The 50% responder rate was 71%. The adverse effects at last follow-up (mean 13 months) included weight gain, myoclonus, and sedation.     

Remacemide hydrochloride: a placebo-controlled, one month, double-blind assessment of its safety, tolerability and pharmacokinetics as adjunctive therapy in patients with epilepsy

Forty patients (33 male, 7 female) with refractory epilepsy were randomized to receive ascending weekly doses of adjunctive remacemide hydrochloride in a b.i.d. or q.i.d. regimen, or placebo for up to 1 month. Assessments included routine physical examination and laboratory tests, recording of adverse events and seizure frequency, and neuropsychological tests. Trough plasma concentrations of concomitant AEDs were measured at weekly intervals. Trough plasma concentrations of remacemide and its desglycinyl metabolite were measured before each dose increment, and complete 24-hour profiles were measured at steady state following administration of 600 mg day(-1)and 1200 mg day(-1). A daily dose of 1200 mg was well tolerated in a q.i.d. regimen and up to 800 mg was well tolerated in a b.i.d. regimen. The most common adverse events were dizziness, diplopia, dyspepsia and abdominal pain. On some occasions, these were considered to be related to raised concentrations of concomitant AEDs. No adverse effects were observed on seizure frequency. Neuropsychology tests revealed no significant changes. Remacemide and the desglycinyl metabolite demonstrated dose proportional pharmacokinetics over the dose range tested.