Adjunctive Therapy For Partial Seizures Research Articles

Perampanel dosage in plasma samples: development and validation of a novel HPLC method with combined UV-Fluorescence detection

Therapeutic drug monitoring (TDM) is a recognized method to improve the quality of use of antiepileptic drugs, such as perampanel (PRP). It is the first compound in the class of selective non-competitive antagonists of AMPA receptors approved in 2012 in Europe and United States for adjunctive therapy of partial seizures. Although several studies have recently underlined that a general reference range for PRP plasmatic concentration might be difficult to propose, TDM of this drug is important in specific clinical situations, as hepatic or renal impairment or co-administration with enzyme-inducing antiepileptics. Several methods have been described in literature for the determination of PRP in different biological matrices, which include the use of liquid chromatography methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection. Here we describe the development and validation of a novel method for the measurement of PRP in plasma samples, based on a HPLC-UV/FL double detection approach and using ketoprofen as internal standard. PRP concentration in a small subset of plasma samples of treated patients was evaluated using both our approach and a commercially available CE-IVD LC–MS/MS method. The results obtained were compared, and confirmed the possibility to use our method as an alternative to LC–MS/MS in clinical routine.

Oxcarbazepine adjunctive therapy for partial seizures in Japanese pediatric patients: a randomized double-blind placebo-controlled study and open-label extension study

Oxcarbazepine adjunctive therapy for partial seizures in Japanese pediatric patients: a randomized double-blind placebo-controlled study and open-label extension study

Clinical efficacy of perampanel for partial-onset and primary generalized tonic-clonic seizures.

Background and purposePerampanel, a selective noncompetitive antagonist at the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is highly effective in a wide range of experimental models. Although initially licensed as adjunctive therapy for partial seizures with or without secondary generalization in patients aged 12 years or older, the US Food and Drug Administration has recently approved its use in the treatment of primary generalized tonic–clonic seizures (PGTCS). This paper reviews the pharmacokinetics, efficacy, and tolerability of perampanel as an antiepileptic drug.ResultsAfter oral ingestion, perampanel is rapidly absorbed (Tmax, 0.5–2.5 hours), has a bioavailability of ~100%, and is highly protein bound (~95%) in plasma. It undergoes extensive (>90%) hepatic metabolism, primarily via cytochrome P450 3A4 (CYP3A4), with a half-life of 48 hours. Carbamazepine and other antiepileptic drugs can enhance its metabolism via induction of CYP3A4. Efficacy of perampanel in focal seizures has been extensively evaluated in Phase II and randomized, placebo-controlled Phase III trials. The efficacy in PGTCS has been reported in one class I study. In the treatment of focal seizures, perampanel showed significant dose-dependent median seizure reductions: 4 mg/d, 23%; 8 mg/d, 26%–31%; 12 mg/d, 18%–35%; and placebo, 10%–21%. The 50% responder rates were 15%–26%, 29%, 33%–38%, and 34%–36% for placebo, 4 mg/d, 8 mg/d, and 12 mg/d perampanel, respectively. Freedom from seizures was recorded in 0%–1.7% of the placebo group, 1.9% of the 2 mg group, 2.6%–4.4% of the 8 mg group, and 2.6%–6.5% of the 12 mg group. For PGTCS, the median seizure reduction was 76.5% for perampanel and 38.4% for placebo. The 50% responder rate was 64.2% for perampanel and 39.5% for placebo. Seizure freedom during maintenance phase was 30.9% for perampanel and 12.3% for placebo. Adverse effects included dose-dependent increases in the frequency of dizziness, somnolence, fatigue, irritability, falls, and probably nausea.ConclusionPerampanel is effective in treating both partial-onset seizures and PGTCS.

Rufinamide: treatment of seizures associated with Lennox-Gastaut syndrome

Rufinamide (RUF) is FDA-approved for adjunctive management of seizures related with Lennox–Gastaut syndrome (LGS). This new anti-epileptic drug (AED) adds to the AEDs previously used for LGS together with valproic acid, lamotrigine, felbamate, and topiramate. Its mechanism of action includes preventive the excessive firing of sodium-dependent action potentials, but RUF also exhibits a broad spectrum of action in animal models. The plasma concentration of other AEDs does not change by the RUF. Dizziness, nausea, diplopia, and ataxia vomiting and somnolence are most common adverse effects taking place with RUF. Status epilepticus has been reported, but were uncommon (0.9%). A recent randomized, double-blinded, placebo-controlled trial of RUF in patients with LGS and generalized seizures, including atypical absence and tonic-atonic seizures, showed a 32.7% median percentage decreased in total seizures and a 42.5% median percentage decreased in tonic-atonic seizures. RUF also considerably decreased seizure severity. RUF has been studied as adjunctive therapy for partial seizures in adults and adolescents. In a study of three healthy volunteers, an oral dose of 600 mg RUF recognized high absorption and monoexponential elimination with a mean half-life (t½) of 9 hrs. Excretion was mainly renal (85%) and complete (98%) within 7 days.

Pregabalin and Libido- Case Reports

Pregabalin is a drug used in UK for the following conditions: peripheral and central neuropathic pain, adjunctive therapy for partial seizures with or without secondary generalization and generalized anxiety disorder. Drugs used to treat anxiety disorders very often do have sexual side effects (e.g. SSRIs, SNRIs, and Benzodiazepines). Patients with generalized anxiety disorder can have an impaired libido due to the direct effect of anxiety. Since mid 2009, when we first started prescribing Pregabalin for patients with a diagnosis of Generalized Anxiety Disorder, two male patients reported enhanced libido after having started treatment with Pregabalin. It would be argued that the Pregabalin mechanism of action might be responsible for these changes. An extensive search of the medical literature conducted in 2010 failed to retrieve any relevant published studies or case reports that comment on the impact of Pregabalin on increased libido. Pregabalin is a drug used in the treatment of neuropathic pain, partial seizures and generalized anxiety disorder. Pregabalin inhibits the release of the excess excitatory neurotransmitters, presumably by binding to the alpha 2 delta proteins of the widely distributed voltage dependent calcium channels in spine and brain. This mechanism is responsible for the anxyolitic, anticonvulsant and antinocioceptive effect. (1) Libido is the term used to describe sexual desire or the psychic and emotional energy related to sexuality. In the accepted sense, libido refers specifically to the mental manifestations of the sexual instinct. (2) Drugs used to treat anxiety disorders very often do have sexual side effects. Patients with generalized anxiety disorder can have an impaired libido due to the direct effect of anxiety. Since 2009, when we have started prescribing Pregabalin for community patients with Generalized Anxiety Disorder, two patients self reported enhanced libido shortly after having started treatment with Pregabalin. The first case is a 42-year-old gentleman who has a diagnosis of Alcohol Dependence, Narcissistic Personality Disorder associated with Generalized Anxiety Disorder. His only pharmacological treatment was Pregabalin 150mg (twice daily) and Quetiapine 50mg (twice daily). Pregabalin was introduced three weeks before he reported increased libido. He was in a stable relationship with a lady he met four years ago. Although he was off work for about 6 months, no significant life events were identified since he started Pregabalin. The above pharmacological treatment was the mainstay of his management plan when he self- reported increased libido.

CHOOSING AMONG ANTIEPILEPTIC DRUGS

Selecting an antiepileptic drug (AED) for treatment of seizures is daunting because there are now 20 from which to choose. Following simple principles allows a systematic approach to drug selection. Efficacy studies provide limited information. For initial monotherapy of partial seizures, high-level evidence exists for the efficacy of lamotrigine, carbamazepine, oxcarbazepine, and topiramate. For initial monotherapy of generalized seizures, high-level evidence is available for valproate, lamotrigine, topiramate, and oxcarbazepine. For initial monotherapy of absence seizures, high-level evidence exists for valproate, lamotrigine, and ethosaximide. All second-generation AEDs have efficacy as adjunctive therapy for partial seizures. AEDs are often useful for comorbid conditions or have properties that should be avoided in some groups. Thus, AEDs should usually be selected on the basis of comorbid conditions, including depression, migraine, chronic pain, obesity, and nephrolithiasis, or patient characteristics, especially for women of childbearing potential and older adults.

Efficacy and safety of levetiracetam as adjunctive therapy in adult patients with uncontrolled partial epilepsy: The Asia SKATE II Study

This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged ≥ 16 years ( N = 251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a ≥ 50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.

A Simple High-Throughput Method for Determination of Pregabalin in Pharmaceutical Dosage Forms using a Microplate Fluorescence Reader

Pregabalin is a structural analogue of γ-aminobutyric acid approved for treatment of neuropathic pain, as adjunctive therapy for partial seizures, and in generalized anxiety disorder. [...]

Pregabalin (PGB) in treatment of oxaliplatin-induced neuropathy

e15045 Background: Oxaliplatin is effective in many GI cancers, especially colorectal cancer (CRC); however, severe neuropathy develops frequently. PGB is a new antiepileptic drug approved as adjunctive therapy of partial seizures in adults, pain from diabetic neuropathy and post-herpetic neuralgia. PGB is structurally related to gabapentin, but unlike gabapentin, it is well absorbed (> 90%) and its absorption is dose independent. In this study, we evaluated the role of PGB in reduction of oxaliplatin- induced neuropathy. Methods: From Nov 2006 to Dec 2008, a total of 23 pts (age range: 50–71 yrs; M:F = 14:9) with GI cancers were treated with PGB upon development of oxaliplatin-induced neuropathy > G2 (NCI-CTC 3.0). Of these pts, 15 received FOLFOX for CRC, 2 EOX for gastric ca and 6 GemOx for pancreatic ca. Neurologic symptoms were evaluated prior PGB and then q 2 wks. PGB was started at 50mg PO tid, and if tolerated, dose was escalated by 50mg increments until symptoms improved up to a maximum of 150mg PO tid. Results: 5/23 pts (22%) were escalated to 150mg PO tid. 12 pts (52%) were escalated to 100mg tid, out of which 7 (58%) continued, 4 (33%) stopped due to no benefit and 1 (8%) stopped due to weight gain. 1/23 (4%) decided to follow 100mg bid. 5/23 (22%) could not be escalated above 50mg tid; 2 continued at this dose and 3 stopped due to CNS side effects. Onset of benefit was observed in 2 - 6 wks. In 3/23 pts (13%), neuropathy improved from G3 to G2, 2/23 (9%) from G3 to G1, 5/23 (22%) from G2 to G1, 6/23 (26%) remained stable at G2 and no pts remained at G3. Most pts continued PGB even beyond disease progression on oxaliplatin (15/23). Among those who continued (15), duration of therapy was 4 -24 months. The best benefit with PGB was seen at a dose of 150mg tid, followed by 100mg tid. The most common non-hematologic toxicities were dizziness (57%), headache (26%), somnolence (22%), dry mouth (17%), ataxia (17%), tremor (13%), peripheral edema (13%), weight gain (13%), blurred vision (13%) and constipation (9%). Hematologic toxicity (G1 thrombocytopenia) was seen in 1 pt (4%) but impact of chemotherapy could not be excluded. Conclusions: PGB significantly reduces the severity of oxaliplatin-induced neuropathy. Larger, placebo-controlled trials assessing safety and efficacy of oral PGB are warranted in pts treated with oxaliplatin. [Table: see text]

Lacosamide: new adjunctive treatment for partial seizures

AbstractLacosamide (Vimpat), which is hypothesised to have a novel dual mode of action, is a new antiepileptic drug licensed as adjunctive therapy for partial seizures. In our New products review Steve Chaplin presents the clinical data relating to its efficacy and adverse effects, and Dr Yvonne Hart comments on its place in treatment. Copyright © 2009 Wiley Interface Ltd

Lamotrigine extended-release as adjunctive therapy for partial seizures

In the article “Lamotrigine extended-release as adjunctive therapy for partial seizures” by D.K. Naritoku et al. ( Neurology ® 2007;69:1610–1618), as a result of changes to the database from audits conducted across all participating study sites, some of the data reported in the manuscript have changed slightly. These audits were conducted by the study sponsor, GlaxoSmithKline, in preparation for response to the FDA approvable letter for the Lamictal XR New Drug Application. The outcome of the audits did not change the overall conclusions of the …

Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety

Background: Zonisamide (ZNS), a sulphonamide derivative, is a new-generation anticonvulsant with multiple potential mechanisms that contribute to its antiepileptic efficacy and may also explain its as yet incompletely assessed utility for non-seizure disorders such as headaches, neuropathic pain, and weight loss. Objective: A review of the pharmacokinetics, pharmacodynamics, evidence for efficacy in different seizure types and non-seizure conditions, adverse effects, and tolerability of ZNS is presented. Methods: A review of all manuscripts published in the English literature on ZNS was performed in preparing this manuscript. Results/conclusions: ZNS has a broad label for use in Japan, while the regulatory bodies in the USA and Europe have approved it for use only as an adjunctive therapy for partial seizures in adults. It has favorable pharmacokinetic characteristics, proven efficacy in seizure disorders, and is well tolerated in long-term use.

Monotherapy for partial epilepsy: focus on levetiracetam

Levetiracetam (LEV), the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED) for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (>/=50% reduction in seizure frequency) of 28%-45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures.

Serum Concentrations of Pregabalin in Patients With Epilepsy: The Influence of Dose, Age, and Comedication

Pregabalin (PGB) is a new antiepileptic drug (AED) approved for adjunctive therapy for partial seizures with and without generalized tonic-clonic seizures and for the treatment of peripheral neuropathic pain in adults. PGB does not bind to plasma proteins and is excreted predominantly unchanged by the kidneys. Previous studies indicated that PGB shows no relevant interactions with other AEDs. The aim of this study was to investigate the influence of PGB dose, patient age, and comedication on the serum concentration of PGB. In total, 198 samples of 167 (adult) inpatients who fulfilled the inclusion criteria (eg, trough concentration, body weight available) were investigated. A patient was considered twice only if the comedication had been changed. The PGB serum concentration (mg/L) in relation to PGB dose/body weight (mg/kg) per day (level-to-dose ratio, LDR, [(mg/L)/(mg/kg)=kg/L]) was calculated and compared for the most frequent drug combinations (n=97). Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that comedication had a slight but significant (P = 0.02) effect on PGB serum concentrations. The median LDR of PGB was 0.29 for PGB + oxcarbazepine (n=16), 0.31 for PGB + carbamazepine (n=20), 0.35 for PGB + levetiracetam (n=11), 0.35 for PGB + lamotrigine (n=15), and 0.39 for PGB + valproic acid + lamotrigine (n=35). Regression analysis including all 198 samples indicated (in accordance with analysis of covariance) that PGB concentrations were lower in combination with enzyme-inducing AEDs (phenytoin, carbamazepine, oxcarbazepine) and were age-dependent (higher in older patients). The PGB dose-concentration relationship was nearly linear (r=0.68, P<0.0001). However, patients on the same PGB dosage per body weight had rather different PGB trough concentrations, which could be explained only in part by age and comedication. The increase of PGB serum concentrations in older patients is in accordance with expectations for drugs that are predominantly renally excreted. Unexpectedly and in contrast to other studies, our data indicate that comedication with enzyme-inducing antiepileptic drugs (eg, carbamazepine) can moderately decrease PGB serum concentrations (about 20% to 30%). Further studies should clarify the effect of age and interactions on PGB concentrations.

Lamotrigine extended-release as adjunctive therapy for partial seizures

To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy. Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained. Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.6% vs 24.5%, p = 0.0001 [corrected] via Wilcoxon test; escalation phase: 29.8% vs 15.6%, p = 0.027; maintenance phase: 58.4% vs 26.8%, p [corrected] < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (44.0% vs 20.8%, p = 0.0002) [corrected] and time to >or=50% reduction in partial seizure frequency (p = 0.0001) [corrected] also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 16%, placebo 18%) [corrected] and dizziness (lamotrigine XR 19%, [corrected] placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant. Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.

Levetiracetam for the Treatment of Neonatal Seizures

Seizures are a common occurrence in the neonatal intensive care unit, especially among low-birth-weight infants. The efficacy and safety of standard anticonvulsants have not been evaluated extensively in the neonate. In addition, there is concern for the adverse effects of phenobarbital on long-term development. Levetiracetam has been a commonly prescribed oral anticonvulsant for the use of adjunctive therapy for partial seizures in adults with favorable tolerability, and it has been recently approved for children older than age 4 years. There are no published studies regarding the safety and efficacy of this medication in the infant population. This report describes the initiation of levetiracetam in 3 infants, aged 2 days to 3 months, for refractory seizures or intolerance to other anticonvulsants. Each patient was without seizure on levetiracetam monotherapy, and there were no adverse effects.

Tiagabine-induced nonconvulsive status epilepticus in an adolescent without epilepsy

Tiagabine (TGB) is a γ-aminobutyric acid (GABA) reuptake inhibitor approved as adjunctive therapy for partial seizures in patients over age 12. It has been used off-label to treat depression, anxiety, bipolar disorder, neuropathic pain, headache, and spasticity. A recent epidemiologic study found that TGB adjunctive therapy does not increase the risk of status epilepticus (SE).1 However, there are now more than a dozen reports of precipitation of nonconvulsive status epilepticus (NCSE) in patients predisposed to seizures, including children,2 or in patients without epilepsy treated chronically with TGB.3 In February 2005, Cephalon, the manufacturer of TGB, issued a warning of the possibility of seizures in patients without epilepsy. We report a case of NCSE after TGB overdose in a 14-year-old girl who neither had epilepsy nor was taking the medication chronically. The present description clarifies some inaccuracies in an earlier report by others of our clinical and EEG findings in this case.4 The patient was a 14-year-old right-handed girl in good health except for mild asthma. On the day of admission, she was found at home obtunded after having ingested an estimated …

Gabapentin in the operating room

Most prescriptions for gabapentin are written for off label conditions—perhaps 90% by some estimates.1 Gabapentin is FDA-approved only for treatment of postherpetic neuralgia and adjunctive therapy for partial seizures. However, there is good evidence for its use in the treatment of chronic pain. There are large, well-designed, placebo-controlled, randomized trials demonstrating analgesic effects for chronic neuropathic pain including diabetic neuropathy.2 There is now evidence for the benefit of gabapentin in a new clinical context, the acute perioperative setting. In this issue of Neurology , Leung et al. lay the foundation for further widening of gabapentin’s indications.3 Severity of postoperative pain and its treatment with opioids is commonly associated with postoperative delirium: as high as 60% after noncardiac surgery.4,5 The incidence is higher in older patients. Level of pain intensity and method of postoperative pain management increase the risk of postoperative delirium more than baseline demographics, cognition, functional status, alcohol intake, or depression.5 The mechanisms of postoperative delirium are not well understood, but this complication is …

Pregabalin action at a model synapse: Binding to presynaptic calcium channel α 2-δ subunit reduces neurotransmission in mice

Pregabalin, (( S)-3-(aminomethyl)-5-methylhexanoic acid, also known as ( S)-3-isobutyl GABA, Lyrica™) is approved for treatment of certain types of peripheral neuropathic pain and as an adjunctive therapy for partial seizures of epilepsy both the EU and the USA and also for generalized anxiety disorder in the EU. Though pregabalin binds selectively to the alpha 2-delta (α 2–δ) auxiliary subunit of voltage-gated calcium channels, the cellular details of pregabalin action are unclear. The high density of α 2−δ in skeletal muscle fibers raises the question of whether pregabalin alters excitation–contraction coupling. We used the mouse soleus neuromuscular junction from mice containing an artificially mutated α 2–δ Type 1 protein (R217A) as a model to examine the effect of pregabalin. Pregabalin reduced nerve-evoked muscle contractions by 16% at a clinically relevant concentration of 10 μM in wildtype mice. When acetylcholine receptors were blocked with curare, pregabalin had no effect on contraction from direct stimulation of muscle, suggesting a lack of drug effects on contraction coupling. Our data are consistent with pregabalin having no effect on striated muscle L-type calcium channel function. However, in mice expressing mutant (R217A) α 2–δ Type 1, there was no significant effect of pregabalin on nerve-evoked muscle contraction. We propose that pregabalin reduces presynaptic neurotransmitter release without altering postsynaptic receptors or contraction coupling and that these effects require high affinity binding to α 2–δ Type 1 auxiliary subunit of presynaptic voltage-gated calcium channels.

Zonisamide ? a review of experience and use in partial seizures

Zonisamide is a modern antiepileptic drug (AED) that is distinguished from other AEDs by its unique structure and broad mechanistic profile. Preclinical studies have reported a range of potential mechanisms of action for zonisamide, such as blocking voltage-gated sodium channels, reduction of T-type calcium channel currents, and enhancement of gamma-aminobutyric acid (GABA)-mediated inhibition, which are indicative of its broad antiseizure effects. Zonisamide has a favorable linear pharmacokinetic profile, a long half-life, and a low incidence of protein-binding interactions with other AEDs. Hepatically metabolized through the cytochrome P450 pathway, zonisamide does not induce its own metabolism or liver enzymes. For more than 2 decades, zonisamide has been extensively used as monotherapy and adjunctive therapy for the treatment of partial and generalized seizures in pediatric and adult patients in Japan. Zonisamide was approved in the USA in 2000 as adjunctive therapy for partial seizures in adults. With over 2 million patient-years of exposure internationally, zonisamide has demonstrated safety and efficacy against a multitude of epilepsy and seizure types, including both partial and generalized seizures. This review focuses on the experience and use of zonisamide in partial seizures, as well as possible new uses for zonisamide.