Adjunctive Therapy In Epilepsy Research Articles

Bioequivalence of Two Perampanel 12mg Tablets in Healthy, Adult, Human Subjects under Fed Conditions - An Open Label, Cross Over Study

Background: Perampanel is a glutamate non-competitive receptor antagonist that is effective as adjunctive therapy for epilepsy. The main objective of the present research is to compare the bioavailability and to evaluate the bioequivalence between the test and reference product. The secondary objective is to assess the safety and tolerability of the drug

Development and validation of dissolution testing of Flunarizine dihydrochloride in tablet dosage form

Background: Flunarizine dihydrochloride is an antivertigo, antimigraine, and adjunctive therapy for epilepsy, available in Indonesia as tablets. However, the dissolution test for the tablet dosage forms is not yet available in the Pharmacopoeia. Objectives: To develop and validate the dissolution method of flunarizine dihydrochloride in tablets. Methods: The dissolution profiles of three products were determined using three media (HCl 0.1N, acetate buffer pH 4.5, and 0.2% Tween 80 solution); two apparatus (basket and paddle); at three agitation speeds (50, 75, and 100rpm). The amount of drug released per unit time was measured by a validated High Performance Liquid Chromatography system. Results: The method using a paddle apparatus at 50rpm in 900mL of 0.1N HCl medium was better hyperdiscriminating with a Q30 value ≥ 75% (p < 0.05). The selected method met the acceptance criteria in terms of precision, accuracy, and specificity.

Brief Literature Review: Glycemic Control With Ketogenic Diet in People With Diabetes.

Evidence does not support a clear preference for a specific eating pattern for people with diabetes, yet recommendations should be evidence-based, standardized, and individualized. Current nutrition guidelines focus on whole foods and dietary patterns rather than specific nutrients (1). The ketogenic eating pattern was initially used as adjunctive therapy for epilepsy (2). However, recent evidence suggests that a ketogenic eating pattern may improve glycemic control in people with type 2 diabetes (2). The macronutrient intake of people on a ketogenic diet predominantly consists of 55–60% fat, 30–35% protein, and <26% carbohydrates, with daily carbohydrate intake ranging from 20 to 50 g based on total caloric intake of 2,000 kcal/day (1–3). The key aspect of the ketogenic eating pattern is the restriction of carbohydrates, which limits the body’s energy intake from glucose. To compensate for the lack of energy derived from glucose, the body produces ketone bodies from fatty acid oxidation to provide an alternative source of energy. The ketone bodies synthesized from fatty acid oxidation include β-hydroxybutyrate, acetoacetate, and acetone. These specific molecules are all able to cross the blood-brain barrier and provide energy to the brain. Additional use of these ketone bodies for energy production can be seen in the kidneys, heart, and muscle tissue (2). The success of the ketogenic eating pattern in people with epilepsy (4,5) has garnered attention for people with other disease states such as type 2 diabetes. Interestingly, ketogenic diets were being developed for treatment of diabetes in the 1910s, at the same time as they were being developed as a treatment for epilepsy (6). Studies have shown patients experiencing rapid weight loss, as well as reductions in A1C and fasting blood glucose (FBG) levels (2). Because of the popular interest in the ketogenic eating pattern among …

A prospective, multicenter, noninterventional study in Taiwan to evaluate the safety and tolerability of lacosamide as adjunctive therapy for epilepsy in clinical practice

RationaleLacosamide (LCM) was initially approved in Taiwan in March 2014 for use as adjunctive therapy for focal impaired awareness seizures and secondarily generalized seizures (SGS) in patients with epilepsy ≥16 years of age. The efficacy and tolerability of adjunctive LCM for the treatment of patients with focal seizures have been demonstrated in randomized, placebo-controlled trials. However, the trials do not reflect a flexible dose setting. This study (EP0063) was conducted to assess the safety and tolerability of LCM in real-world clinical practice in Taiwan. Effectiveness of LCM was also assessed as an exploratory objective. MethodsEP0063 was a multicenter, prospective, noninterventional study with an expected observation period of 12 months ± 60 days. Eligible patients were ≥16 years of age, had focal impaired awareness seizures and/or SGS (in line with approved indication in Taiwan at the time of the study), were taking at least one concomitant antiseizure medication (ASM), and had at least one seizure in the 3 months before baseline. Patients were prescribed LCM by their treating physician in the course of routine clinical practice. The primary safety variable was treatment-emergent adverse events (TEAEs) spontaneously reported to, or observed by, the treating physician. Based on safety data from previous studies of LCM and known side effects of other ASMs, certain TEAEs (including but not limited to cardiac and electrocardiogram, suicidality, and rash related terms) were analyzed separately. Effectiveness variables included Clinical Global Impression of Change (CGIC) and change in 28-day seizure frequency from baseline to 12 months (or final visit), and freedom from focal seizures. ResultsA total of 171 patients were treated with LCM, of whom 139 (81.3%) completed the study. The Kaplan–Meier estimated 12-month retention was 82.9%. Patients had a mean (standard deviation [SD], range) age of 38.5 (14.0, 16–77) years, and 96 (56.1%) were male. Patients were taking a mean (SD, range) of 2.8 (1.1, 1–6) ASMs at baseline. Mean (SD, range) duration of LCM treatment was 288.7 (111.9, 2–414) days, and the mean (SD, range) daily dosage of LCM was 205.0 (82.7, 50.0–505.2) mg/day. Overall, 95 (55.6%) patients reported at least one TEAE, most commonly dizziness (33 [19.3%] patients). Drug-related TEAEs were reported in 74 (43.3%) patients, and drug-related TEAEs leading to discontinuation of LCM were reported in 14 (8.2%) patients. Two (1.2%) patients died during LCM treatment, which were considered not related to LCM. Two (1.2%) patients had suicidality-related TEAEs; these TEAEs were considered either not related to LCM or the relationship was not recorded. Rash-related TEAEs were reported in five (2.9%) patients (considered LCM-related in two patients). Based on the CGIC, at 12 months (or final visit), 109 (63.7%) patients were considered to have improved, 54 (31.6%) had no change, and the remaining eight (4.7%) were minimally worse. At 12 months (or final visit), the median percentage change in focal seizure frequency was –50.0. During the first 6 months of the study, 21 (12.3%) patients were free from focal seizures; 37 (21.6%) patients were free from focal seizures in the last 6 months of the study; and 14 (8.2%) were free from focal seizures for the full 12 months of the study. ConclusionsResults of this prospective, noninterventional study suggest that adjunctive LCM was generally safe and well tolerated in this patient group in real-world practice in Taiwan. Effectiveness was also favorable, with more than 60% of patients considered to be improved by their physician at 12 months (or final visit).

The tolerability and safety profile of eslicarbazepine acetate in neurological disorders

ObjectivesThis study aimed to assess the tolerability and safety profile of eslicarbazepine acetate (ESL). MethodsPlacebo controlled, double-blind randomized controlled trials (RCTs) were enrolled by searching Pubmed, Embase, Cochrane Online Library, and clinicaltrial.gov. Studies evaluating the safety of ESL on any neurological disorders were included. Adverse events (AEs), serious AEs and AEs-related withdrawals were pooled by direct or indirect meta-analysis. ResultsA total of 4067 patients in 13 RCTs (5 for refractory partial epilepsy, 2 for bipolar I disorder, 1 for migraine, 1 for fibromyalgia, 2 for diabetic neuropathic pain, and 2 for post-herpetic neuralgia) were included. Meta-analysis revealed that ESL treatment had a higher incidence of serious AEs and AEs-related withdrawals than the placebo. Of 35 reported AEs, 13 were significantly associated with ESL treatment, including blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, hyponatraemia, increased gamma-glutamyl transferase, and dysarthria. Subgroup analysis revealed that dizziness was the only AE significant at 400 mg/day, while diplopia, nausea, vomiting, dizziness, somnolence, rash, and hyponatremia at 800 mg/day, and blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, and hyponatremia at 1200 mg/day were significant. Adjunctive use of ESL in refractory epilepsy significantly led to higher risk for vestibulocerebellar AEs than other disorders. ConclusionsESL treatment was related to a range of AEs, especially at high doses or when used as adjunctive therapy in epilepsy. While the majority of AEs of ESL were related to the vestibulocerebellar system, hyponatremia and rash should also be noted by clinicians.

Efficacy upon 12-weeks after achievement of maximal dose and tolerability of lacosamide as an adjunctive therapy in epilepsy: Real world clinical experience

Lacosamide (LCM) is a new generation antiepileptic drug. It has only been available in Asia in recent years. A retrospective study at two hospitals in Hong Kong was performed to investigate the post-marketing efficacy and tolerability of the drug. A total of 81 subjects were recruited, among which 88% had drug-resistant epilepsy. The most common type of epilepsy was focal with unknown etiology. All patients used LCM as adjunctive therapy. The 50% responder rate was 42% at 12 weeks after achievement of maximal dose of LCM. No specific factor correlated with responsiveness including concomitant enzyme-inducing or sodium channel blocking anticonvulsants. Withdrawal rate within first 12 weeks after drug initiation was 14% while that at any time upon follow-up was 23%. Two cases of uncommon adverse reaction of myoclonus were also reported. The mechanism was postulated to be the sodium channel inhibiting action of LCM. Our study has shown LCM to have comparable efficacy and tolerability in post-marketing experience when compared with the landmark randomized controlled trials.

Pregabalin prescriptions in the United Kingdom: a drug utilisation study of The Health Improvement Network (THIN) primary care database.

In Europe, pregabalin is approved for treatment of neuropathic pain, general anxiety disorder (GAD) and as adjunctive therapy for epilepsy. The purpose of this study was to assess utilisation of pregabalin in the UK, including patients with a recorded history of substance abuse, from a large general practice database. This observational drug utilisation study (DUS) analysed pregabalin prescription data from the UK Health Improvement Network primary care database between September 2004 and July 2009. Patient demographics, diagnoses (by READ codes) and pregabalin dosing data were collected. Diagnosis codes were used as proxy for approved indication for pregabalin. A cohort of 18,951 patients was prescribed pregabalin; dosing information was available for 13,480 (71.1%). Median age of patients was 58 years, and majority were female (60.1%). Median (interquartile range) prescribed average daily dose (ADD) of pregabalin for all patients was 150.0 (162.5) mg/day; this was highest in patients with epilepsy (191.9 mg/day), followed by neuropathic pain (158.0 mg/day) and GAD (150.0 mg/day). Only 1.0% (136/13,480) of patients were prescribed an ADD of pregabalin over the maximum approved dose of 600 mg/day. Of these, 18.4% (25/136) of patients had a history of substance abuse compared with 14.0% (1884/13,480) in the full population. Data from this DUS indicated that the majority of pregabalin prescribing in the UK was consistent with product labelling. The proportion of patients with prescribed ADD > 600 mg/day was small and with a similar proportion with a history of substance abuse as in the full population.

Randomized-controlled trials of levetiracetam as an adjunctive therapy in epilepsy of multiple seizure types

This meta-analysis aimed to systematically collect and synthesize the current evidence regarding the efficacy and tolerability of levetiracetam (LEV) as an adjunctive therapy for adults and children suffering from idiopathic and secondary epilepsy of multiple seizure types. We selected randomized-controlled trials (RCT) of LEV as an adjunctive therapy in epilepsy according to predefined criteria. Outcome measures included a ⩾50% reduction in seizure frequency, seizure freedom, and adverse events. Thirteen RCT were analyzed. Results showed that the efficacy of adjunctive LEV was superior to placebo both in achieving ⩾50% reduction in seizure frequency (pooled odds ratio [OR] 3.36, 95% confidence interval [CI] 2.78–4.07, Z=12.46; p<0.00001) and seizure freedom (pooled OR 4.72, 95% CI 2.96–7.54, Z=6.50; p<0.00001). The heterogeneity was mild (chi-squared=12.28, I2=2% in ⩾50% reduction in seizure frequency, and chi-squared=0.49, I2=0% in seizure freedom). Subgroup analysis suggested similar effects across different dosages in adults. The incidence of adverse reactions was not significantly different between the LEV group and the placebo group. The adverse events of relatively high incidence in the LEV group included somnolence, agitation, dizziness, asthenia, and infection. Incidence of serious adverse reaction such as rash and white blood cells and platelets decreasing was quite low. Adjunctive therapy with LEV was superior to placebo in reducing the frequency of seizures in patients with partial and idiopathic generalized epilepsy with effect in both adults and children, and demonstrated good tolerance in patients with epilepsy.

GABAA Receptor Physiology and Its Relationship to the Mechanism of Action of the 1,5-Benzodiazepine Clobazam

Clobazam was initially developed in the early 1970s as a nonsedative anxiolytic agent, and is currently available as adjunctive therapy for epilepsy and anxiety disorders in more than 100 countries. In October 2011, clobazam (Onfi™; Lundbeck Inc., Deerfield, IL, USA) was approved by the US FDA for use as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is a long-acting 1,5-benzodiazepine whose structure distinguishes it from the classic 1,4-benzodiazepines, such as diazepam, lorazepam and clonazepam. Clobazam is well absorbed, with peak concentrations occurring linearly 1-4 hours after administration. Both clobazam and its active metabolite, N-desmethylclobazam, are metabolized in the liver via the cytochrome P450 pathway. The mean half-life of N-desmethylclobazam (67.5 hours) is nearly double the mean half-life of clobazam (37.5 hours). Clobazam was synthesized with the anticipation that its distinct chemical structure would provide greater efficacy with fewer benzodiazepine-associated adverse effects. Frequently reported adverse effects of clobazam therapy include dizziness, sedation, drowsiness and ataxia. Evidence gathered from approximately 50 epilepsy clinical trials in adults and children indicated that the sedative effects observed with clobazam treatment were less severe than those reported with 1,4-benzodiazepines. In several studies of healthy volunteers and patients with anxiety, clobazam appeared to enhance participants' performance in cognitive tests, further distinguishing it from the 1,4-benzodiazepines. The anxiolytic and anticonvulsant effects of clobazam are associated with allosteric activation of the ligand-gated GABA(A) receptor. GABA(A) receptors are found extensively throughout the CNS, occurring synaptically and extrasynaptically. GABA(A) receptors are composed of five protein subunits, two copies of a single type of α subunit, two copies of one type of β subunit and a γ subunit. This arrangement results in a diverse assortment of receptor subtypes. As benzodiazepine pharmacology is influenced by differences in affinity for particular GABA(A) subtypes, characterizing the selectivity of different benzodiazepines is a promising avenue for establishing appropriate use of these agents in neurological disorders. Molecular techniques have significantly advanced since the inception of clobazam as a clinical agent, adding to the understanding of the GABA(A) receptor, its subunits and benzodiazepine pharmacology. Transgenic mouse models have been particularly useful in this regard. Comparative studies between transgenic and wild-type mice have further defined relationships between GABA(A) receptor composition and drug effects. From such studies, we have learned that sedating and amnesic effects are mediated by the GABA(A) α(1) subunit, α(2) receptors mediate anxiolytic effects, α subunits are involved with anticonvulsant activity, α(5) may be implicated in learning and memory, and β(3) subunit deficiency decreases GABA inhibition. Despite progress in determining the role of various subunits to specific benzodiazepine pharmacological actions, the precise mechanism of action of clobazam, and more importantly, how that mechanism of action translates into clinical consequences (i.e. efficacy, tolerability and safety) remain unknown. Testing clobazam and 1,4-benzodiazepines using a range of recombinant GABA(A) receptor subtypes would hopefully elucidate the subunits involved and strengthen our understanding of clobazam and its mechanism of action.

Safety and Tolerability of Lamotrigine

The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens-Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo-controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders.

Recent advances in adjunctive therapy for epilepsy: Focus on sodium channel blockers as third-generation antiepileptic drugs

Voltage-gated sodium channel blockers like phenytoin and carbamazepine have long been used in the treatment of epilepsy. Brain sodium channels continue to be an important target of many newer second-generation (fosphenytoin, oxcarbazepine, lamotrigine, felbamate, topiramate, zonisamide) and third-generation (eslicarbazepine, brivaracetam, carisbamate, fluorofelbamate, elpetrigine, lacosamide, rufinamide, safinamide, vinpocetine) antiepileptic drugs (AEDs). Some of the newer drugs show either state-dependent antiepileptic action or sodium channel subtype selectivity, although most agents do not differentiate between these channel subtypes. The present review highlights the preclinical and clinical efficacy, pharmacokinetics, drug interactions and adverse event profiles. It also addresses AED selection of sodium channel blockers that constitutes the third generation of AEDs.

The SKATE™ study: An open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.

Sunday, December 3, 2006 Poster Session II 7:30 a.m.–4:30 p.m.

Sunday, December 3, 2006 Poster Session II 7:30 a.m.–4:30 p.m.

THE SKATE STUDY: INTERIM ANALYSIS

SUMMARY The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study is a continuing phase IV open-label evaluation of the antiepileptic drug levetiracetam (Keppra) as an adjunctive therapy in adult patients with uncontrolled partial seizures. The study, which began in April 2000, is scheduled to include 1400 patients from 300 centres in 16 countries. An interim analysis of the first 731 patients from 117 centres in nine countries treated over a 16-week period showed that seizure frequency was reduced by half or more in 49% of patients across all seizure types. A substantial 17.2% of patients achieved complete freedom from seizures. Levetiracetam was well tolerated overall. Adverse events were predominantly mild to moderate and rarely led to discontinuation. The most commonly reported symptoms were asthenia, somnolence, headache and dizziness.

The Pharmacoeconomics of the New Antiepileptic Drugs

The Pharmacoeconomics of the New Antiepileptic Drugs

Adjunctive therapy in epilepsy: a cost-effectiveness comparison of two AEDs

The objective of this study was to compare the relative cost-effectiveness of two AEDs by a prospective clinical audit. Patients starting on the adjunctive therapies lamotrigine and topiramate were recruited from the out-patient epilepsy clinics at Queen Square. Three interview were scheduled: baseline; three months follow-up and six months from baseline. Of the 81 patients recruited, a total of 73 patients completed all three interviews. An intention to treat analysis was performed on the data. Seizure severity and frequency were assessed using the National Hospital Seizure Severity Scale. Side-effects, adverse events and reasons for stopping medication were also recorded.At the third interview, a total of 47/73 (64%) were still on the prescribed adjunctive drug. Outcome was assessed by two methods: the >50% seizure reduction cited in the literature and a more stringent assessment of patient ‘satisfaction’ which we defined operationally on clinical criteria. Using this definition, a total of 10/73 (14%) patients were ‘satisfied’. The relative costs of starting patients on each of the two AEDs were calculated, both drug costs and the costs of adverse events (the latter were defined as events requiring urgent medical attention). The costs of the two drugs were compared. A number of methodological issues relating to cost comparison are discussed. Outcome and pharmaco-economic studies need to assess more than reduction in number of seizures. They should take into account variables important for quality of life including side-effects and adverse events.

Adjunctive therapy in epilepsy with new antiepileptic drugs: is it of any value?

A total of 97 patients were recruited into a prospective, follow-up study after they were prescribed an adjunctive antiepileptic drug. The patients were followed up over a 6-month period. The interview included questions on Quality of Life, side-effects, adverse events and seizure frequency and severity. We operationally defined patients 'satisfaction' as (i) still on new drug; (ii) experiencing no side-effects (iii) experiencing no adverse events and (iv) had a greater than 50% reduction in seizures. A total of 13 patients (17%) reported being 'satisfied' according to our operational definition.

Electroconvulsive Therapy for Epilepsy and Major Depression

In this first report of electroconvulsive therapy (ECT) for the simultaneous treatment of seizures and depressive episodes, the authors discuss the use of ECT in the treatment of complex-partial seizures and major depression in a geriatric patients who refused antidepressant and antiepileptic medication. ECT has numerous anticonvulsant effects, including elevated seizure threshold and decreased seizure duration, which make it a useful adjunctive therapy in epilepsy that is refractory or not amenable to treatment with medication.

Adjunctive therapy in epilepsy: a cost-effectiveness comparison of alternative treatment options

A pharmaco-economic study of the administration of adjunctive therapy in patients with chronic epilepsy is described. A decision-analytic model has been used, which represents the consequences of treatment over a 1-year time period, when one of three drugs is used first. The cost-effectiveness ratio for clobazam, lamotrigine and vigabatrin have been calculated. The expected cost per patient of treatment over the 1-year period was up to 50% higher with vigabatrin and lamotrigine compared with clobazam, with a cost-effectiveness ratio around 40% higher.

The long-term effect of clobazam as adjunctive therapy in epilepsy.

Thirty drug-resistant epilepsy patients were given 20-30 mg of clobazam in addition to their other anticonvulsants and followed up for 2-3 years in an open-ended study. Fit frequency was markedly reduced in 43% of patients, few side effects occurred and psychological parameters including the Crown-Crisp questionnaire, showed improvement. It therefore seems that clobazam is a useful additional drug added to conventional anticonvulsant regimes.