Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies.

OBJECTIVE: Cognitive and psychiatric adverse events in patients with epilepsy are important determinants of therapeutic outcomes and patient quality of life. We assessed the relationship between adjunctive cenobamate treatment and selected cognitive and psychiatric treatment-emergent adverse events (TEAEs) in adults with uncontrolled focal epilepsy. METHODS: This was a retrospective analysis of pooled populations of patients with focal epilepsy from two phase 2, randomized, double-blind clinical trials; two open-label extensions (OLEs) of those trials; and a long-term, open-label, phase 3 safety study. Occurrence of cognitive and psychiatric TEAEs in patients treated with adjunctive cenobamate or placebo during double-blind treatment were evaluated. Exposure-adjusted incidence rates of the cognitive and psychiatric TEAEs, defined as the number of TEAEs per patient-year of treatment, during up to 7 years of long-term adjunctive cenobamate treatment, were determined in the pooled OLE and phase 3 patient populations. RESULTS: The pooled randomized trials resulted in a population of 442 patients treated with cenobamate (100 mg/day: n = 108; 200 mg/day: n = 223; 400 mg/day: n = 111) and 216 placebo-treated patients. The combined open-label studies resulted in pooled populations of cenobamate-treated patients ranging from n = 1690 during Year 1 to n = 103 during Year 7. Among cenobamate-treated (all doses) and placebo-treated patients during double-blind treatment, cognitive TEAEs were reported by ≤ 1.9 % (range, 0 %-1.9 %) and ≤ 0.5 % (range, 0 %-0.5 %), respectively, and psychiatric TEAEs by ≤ 3.6 % (range, 0 %-3.6 %) and ≤ 3.2 % (range, 0 %-3.2 %), respectively. During up to 7 years of open-label adjunctive cenobamate treatment, exposure-adjusted incidence rates of cognitive and psychiatric TEAEs were < 0.018 and < 0.038 events per patient-year, respectively. Discontinuation of adjunctive cenobamate due to cognitive or psychiatric TEAEs assessed in this study during double-blind or open-label treatment occurred in ≤ 0.3 % and ≤ 1.7 % of patients, respectively. CONCLUSIONS: Cognitive and psychiatric TEAEs were reported by similar numbers of cenobamate- and placebo-treated patients during double-blind adjunctive cenobamate treatment (< 4 % of patients), and exposure-adjusted incidence rates of these TEAEs remained low during open-label cenobamate treatment for up to 7 years. Treatment discontinuations due to these TEAEs were rare. The results of this post-hoc analysis indicate that adjunctive cenobamate treatment exhibits a low incidence of cognitive or psychiatric TEAEs in patients with uncontrolled focal seizures.

Efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate in patients with focal to bilateral tonic-clonic seizures.

OBJECTIVE: To report the efficacy, safety, and tolerability of adjunctive eslicarbazepine acetate (ESL) treatment in reducing focal to bilateral tonic-clonic seizures (FBTCS). METHODS: Data were pooled from 3 randomized clinical trials (RCTs) of adjunctive ESL in patients with focal seizures. Patients treated with 800 or 1200 mg/day ESL and who experienced ≥ 1 FBTCS during baseline were included. Efficacy was measured using FBTCS standardized seizure frequency (SSF), responder rates (≥50%, ≥75%, and 100%), and time to first FBTCS. Adverse events (AEs) were tabulated for each subgroup. RESULTS: Of the original 1447 patients, 438 patients in the safety population were included with ≥ 1 FBTCS at baseline (efficacy population, n = 429). Patients with ≥ 2 FBTCS (safety, n = 354; efficacy, n = 346) and ≥ 3 FBTCS (safety, n = 294; efficacy, n = 288) at baseline were also analyzed. The 1200 mg/day ESL group experienced lower least squares mean SSF vs placebo in patients with ≥ 1 baseline FBTCS (P = 0.0395) and ≥ 3 baseline FBTCS (P = 0.0091). The 50% responder rates improved for 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.005; ≥2 FBTCS, P = 0.0063; ≥3 FBTCS, P = 0.0016). The 75% responder rates improved with 1200 mg/day ESL vs placebo (≥1 FBTCS, P = 0.0315; ≥2 FBTCS, P = 0.0215; ≥3 FBTCS, P = 0.0099), and with 800 mg/day ESL for ≥ 2 FBTCS at baseline (P = 0.0486). The 100% responder rate was higher in patients treated with 1200 mg/day ESL (not significant). Time to first FBTCS was longer with both 800 (P = 0.0008) and 1200 mg/day (P = 0.0020) ESL vs placebo for the ≥ 1 FBTCS subgroup, and with 1200 mg/day ESL for ≥ 2 FBTCS (P = 0.0060) and ≥ 3 FBTCS (P = 0.0152) subgroups. Overall, AEs occurred at similar rates across subgroups, and were lower than the original RCTs. CONCLUSION: Adjunctive ESL produced a robust response in patients with FBTCS, a seizure type associated with SUDEP and high injury rates. Adjunctive ESL was well tolerated in patients who experienced FBTCS.

The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters.

Nasal administration of treatments for neurologic conditions, including rescue therapies to treat seizure clusters among people with epilepsy, represents a meaningful advance in patient care. Nasal anatomy and physiology underpin the multiple advantages of nasal administration but also present challenges that must be addressed in any successful nasal formulation. Nasal cavity anatomy is complex, with a modest surface area for absorption that limits the dose volume of an intranasal formulation. The mucociliary clearance mechanism and natural barriers of the nasal epithelia must be overcome for adequate absorption. An extensive vasculature and the presence of olfactory nerves in the nasal cavity enable both systemic and direct-to-brain delivery of drugs targeting the central nervous system. Two intranasal benzodiazepine rescue therapies have been approved by the US Food and Drug Administration for seizure-cluster treatment, in addition to the traditional rectal formulation. Nasal sprays are easy to use and offer the potential for quick and consistent bioavailability. This review aims to increase the clinician's understanding of nasal anatomy and physiology and of the formulation of intranasal rescue therapies and to facilitate patient education and incorporate intranasal rescue therapies for seizure clusters (also known as acute repetitive seizures) into their seizure action plans.

Prospective randomized trial of antithrombotic strategies following great saphenous vein ablation using injectable polidocanol endovenous microfoam (Varithena).

OBJECTIVE: Postablation deep vein thrombosis (DVT) represents a potentially serious complication after Varithena polidocanol endovenous microfoam (PEM) ablation. The following primary outcomes were assessed: whether (1) adjunctive apixaban anticoagulation or (2) mechanical deep venous system (DVS) saline flushing could decrease saphenofemoral junction (SFJ) thrombus extension (postablation superficial thrombus extension [PASTE]) and/or DVT compared with compression alone, after great saphenous vein (GSV) PEM ablation. METHODS: Varithena 1% PEM ablation patients were randomized to (1) SFJ compression, (2) compression and DVS saline flushing, or (3) compression, DVS saline flushing, and 5 days of postprocedural 5 mg oral apixaban anticoagulation twice daily. Duplex imaging was obtained 7 to 10 days after PEM ablation and PASTE/DVT incidence (primary end point) was compared between groups at this time point. RESULTS: We treated 304 limbs in 257 patients with PEM. Overall, 103 limbs received SFJ compression (group C, 33.8%), 101 received compression and deep venous flushing (group D, 32.9%), and 100 received compression, deep flush, and anticoagulation (group A, 33.2%). Mean ultrasound follow-up time was 9.7 days (all patients) with a primary GSV closure rate of 92.4%. SFJ PASTE (II-IV) occurred in 0.9%, 1.0%, and 0% (groups C, D, and A, respectively). DVT occurred in 16.7%, 14.7%, and 1.98% (groups C, D, and A; χ2, P = .002). Patients in group A receiving apixaban anticoagulation had a significant reduction in DVT compared with patients in group C (1.98% vs 16.7%, χ2; P < .001); likewise, patients in group A had a significantly decreased DVT occurrence compared with group D (14.7% vs 1.98%; χ2, P = .00162), whereas patients in groups C and D were not statistically different (16.7% vs 14.7%; χ2, P = .60). CONCLUSIONS: (1) Neither adjunctive DVS flushing nor anticoagulation decreased clinically relevant SFJ PASTE (II-IV) incidence, which remained similarly low across all groups and ranged between 0% and 1%, regardless of adjunctive DVS flushing or anticoagulation. This rate was significantly lower than prior reports (2.3%-4.1%). (2) DVS flushing had no influence on the rate of DVT. Observed PEM-induced DVT incidence using SFJ compression alone or compression with DVS flushing (16.7% and 14.7%, respectively) was significantly higher than prior reports (2.5%-9.6%). This finding may relate to the greater extent of AK/BK GSV territory treated in the present study. (3) Five days of postprocedural oral apixaban anticoagulation, 5 mg given twice daily, significantly decreased DVT occurrence to 1.98%, compared with nonanticoagulated patients (16.7%). This finding is comparable with the DVT rates reported after endovenous thermal ablation (0.7-1.7%). (4) Postprocedural apixaban anticoagulation may have a significant preventive role in decreasing DVT occurrence after PEM ablation.

A systematic review of seizure clusters: Prevalence, risk factors, burden of disease and treatment patterns.

Seizure clusters (SCs) are episodes of consecutive seizures that occur within a short period. The treatment patterns of rescue medications (RMs), as well as the burden of SCs, have not been assessed. A systematic literature search on Embase.com (in PubMed and Embase), supplemented with keyword-based and bibliographic searches, identified 44 articles for disease burden, three treatment guidelines, and three articles for treatment patterns. Common SC definitions were ≥3 seizures/24 h, ≥2/24 h and ≥2/6 h. The rate of SCs in prospective studies ranged from 21.7 %-42.5 %. The frequency of status epilepticus (SE) was higher in SC patients. SCs were associated with higher seizure frequency, higher risk of treatment resistance, and lower likelihood of seizure remission. Quality of life (QoL) was lower in children with SCs than in those with isolated seizures. Seizure-related hospitalization was more common in SC than non-SC patients. SCs adversely affected the productivity of patients and their caregivers. In outpatients with SCs, RMs were prescribed to 24.6 %-89.6 % and utilized by 15.6 %-44.5 %, with rates being higher in children. Key reasons for RM under-utilization were lack of seizure action plans, poor physician-patient communication, and concerns with administration route. In conclusion, SCs are associated with a higher risk of SE, treatment resistance, and low rate of seizure remission. They adversely affect patient and caregiver QoL and work productivity. However, RMs are under-prescribed, and there is an urgent need to improve recognition of SCs, improve use of seizure action plans, and remove barriers to RM use.

Long-term safety of adjunctive cenobamate in patients with uncontrolled focal seizures: Open-label extension of a randomized clinical study.

OBJECTIVE: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). METHODS: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis. RESULTS: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. SIGNIFICANCE: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs.

Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

Expert opinion: Proposed diagnostic and treatment algorithms for Lennox-Gastaut syndrome in adult patients.

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy diagnosed in childhood that persists through adolescence and into adulthood. While the characteristics of LGS in pediatric patients are well defined, including "drop attacks", interictal slow spike and wave electroencephalogram (EEG) activity, and intellectual disability, these features can evolve over time, and different EEG activities may be present in adult patients with LGS. This may result in missed diagnoses in these patients and subsequent challenges for the adequate treatment of their seizures. Based on discussions held during the LGS Transition of Care advisory board meeting and thereafter, we developed proposed diagnostic and treatment algorithms for LGS in adult patients. We highlight readily available assessments to facilitate diagnosis of LGS, based on past medical history and physical examination. The LGS diagnostic algorithm recommends that clinicians consider the occurrence of wider seizure types and abnormal EEG activities to be potentially indicative of LGS. Seizure types may include atypical absence seizures, myoclonic seizures, focal seizures, and tonic-clonic seizures, and EEG may demonstrate background slowing, focal or multifocal epileptiform discharges, and diffuse fast rhythms during sleep, among other activities. Extended EEG during sleep and video-EEG should be used in equivocal cases. Treatment of LGS in adult patients should incorporate both antiseizure drug (ASD) therapy and nonpharmacologic approaches. Frequent reassessment of patients is considered a central aspect. ASDs were categorized based on order of preference for use in the treatment of LGS; Tier 1 comprises recommended first-line ASDs, and includes valproate, clobazam, lamotrigine, rufinamide, topiramate, and cannabidiol. Other treatment options include diet, neurostimulation, and surgical approaches. Developments with the potential to improve diagnosis in the future include genetic screening, while novel ASDs and advances in neurostimulation techniques may provide valuable treatment options. These algorithms should be frequently revisited to incorporate improved techniques and therapies.

Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs. METHODS: In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment. RESULTS: Two hundred twenty-two patients were randomized; 113 received cenobamate and 109 received placebo; and 90.3% and 90.8% of patients, respectively, completed double-blind treatment. Median baseline seizure frequency was 6.5 in 28 days (range 0-237). Compared to placebo, cenobamate conferred a greater median percent seizure reduction (55.6% vs 21.5%; p < 0.0001) The responder rate (≥50% reduction in seizure frequency) was 50.4% for cenobamate and 22.2% for placebo (p < 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%). CONCLUSION: Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated. CLINICALTRIALSGOV IDENTIFIER: NCT01397968. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

Comparison of hand-held acoustic Doppler with point-of-care portable color Doppler ultrasound in the assessment of venous reflux disease.

OBJECTIVE: Diagnostic-quality portable color Doppler ultrasound (PCD) offers convenient point-of-care venous reflux disease (VRD) diagnosis. Philips Lumify (Philips N.V., Best, The Netherlands), a high-fidelity broadband linear array transducer (4-12 MHz frequency), connects through a web-enabled smartphone or tablet to cloud software and offers B-mode and color Doppler imaging without pulsed wave Doppler capability. The aims of the study were to compare hand-held acoustic Doppler (HHD) vs PCD diagnostic performance using conventional duplex ultrasound (DUP) as the "gold standard" for VRD assessment, to assess effects of body mass index (BMI) and disease severity on diagnostic performance of HHD and PCD, and to determine whether PCD offers any diagnostic improvement over HHD in VRD assessment. METHODS: There were 241 patients (65 male, 176 female; mean age, 55.5 ± 15.5 years; mean BMI, 32.2 ± 7.9 kg/m2). DUP (447 legs), PCD (262 legs), and HHD (217 legs) studied the great saphenous vein at above-knee (AK) and below-knee (BK) levels. A phlebologist performed HHD, whereas PCD and DUP were performed sequentially (PCD first) by an experienced technologist and interpreted independently. PCD was done blinded to DUP results. DUP findings were analyzed blinded to HHD and PCD results. Venous reflux was dichotomously assessed as <2 seconds and >2 seconds. RESULTS: HHD improves from moderate to good sensitivity from AK level (68%) to BK level (94%) but suffers poor specificity that declines significantly from AK level (50%) to BK level (12%; P < .05). HHD positive predictive value exceeds its negative predictive value (NPV) and remains unchanged from AK level (71%) to BK level (72%). HHD NPV remains consistently poor at AK (48%) and BK (42%) levels. PCD has similar sensitivity from AK level (69%) to BK level (74%), better AK level (79%) vs BK level (58%) specificity (P < .05), similar positive predictive value for AK (76%) and BK levels (78%), and better NPV for AK level (72%) vs BK level (53%; P < .05). BMI range (<30 kg/m2 vs ≥ 30 kg/m2) did not influence diagnostic performance of HHD and PCD significantly. HHD and PCD specificity was higher for Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) class <4 compared with CEAP class ≥4 (P < .05). CONCLUSIONS: The relative diagnostic performance of HHD and PCD is highly dependent on insonation level. PCD advantages compared with HHD are marginally greater specificity at AK and BK levels and better NPV at AK level. Compared with HHD, PCD's disadvantage is lower sensitivity at BK level. Both HHD and PCD have higher specificity at AK level than at BK level. Overall, PCD offers only moderate sensitivity and specificity, making it inadequate for exclusion of significant venous reflux. Neither obesity nor CEAP class significantly influenced the general diagnostic performance of PCD or HHD.

In vivo Serum Enabled Production of Ultrafine Nanotherapeutics for Cancer Treatment.

Systemic delivery of hydrophobic anti-cancer drugs with nanocarriers, particularly for drug-resistant and metastatic cancer, remain a challenge because of the difficulty to achieve high drug loading, while maintaining a small hydrodynamic size and colloid stability in blood to ensure delivery of an efficacious amount of drug to tumor cells. Here we introduce a new approach to address this challenge. In this approach, nanofibers of larger size with good drug loading capacity are first constructed by a self-assembly process, and upon intravascular injection and interacting with serum proteins in vivo, these nanofibers break down into ultra-fine nanoparticles of smaller size that inherit the drug loading property from their parent nanofibers. We demonstrate the efficacy of this approach with a clinically available anti-cancer drug: paclitaxel (PTX). In vitro, the PTX-loaded nanoparticles enter cancer cells and induce cellular apoptosis. In vivo, they demonstrate prolonged circulation in blood, induce no systemic toxicity, and show high potency in inhibiting tumor growth and metastasis in both mouse models of aggressive, drug-resistant breast cancer and melanoma. This study points to a new strategy toward improved anti-cancer drug delivery and therapy.

Long-term safety and efficacy following conversion to eslicarbazepine acetate monotherapy in adults with focal seizures.

OBJECTIVE: To assess the long-term safety and efficacy of eslicarbazepine acetate (ESL) monotherapy in adults with focal seizures (FS). METHODS: Study 050 was a long-term, multicenter, open-label (OL) safety extension of two conversion-to-ESL monotherapy studies in adults with refractory FS. After participating in Study 045 or 046, patients started on ESL 1600 mg once daily (QD) (or 1200 mg if they previously had a dose reduction), and could adjust the dose 400 mg/week to a dose between 800-2400 mg QD. Patients could add up to two additional antiepileptic drugs (AEDs). This post-hoc analysis focuses on the actual monotherapy subgroup, which included patients in Studies 045/046/050 who did not add additional AEDs. Study endpoints included treatment retention time, time on ESL monotherapy, change in standardized seizure frequency (SSF), change in quality of life (QoL) in epilepsy (QOLIE-31) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores, and incidence of treatment-emergent adverse events (TEAEs); serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs related to allergic reaction, hyponatremia and thyroid function were also evaluated. RESULTS: There were 274 patients in the Study 050 full intent-to-treat (ITT) population and 140 patients in the actual monotherapy subgroup. Median treatment retention time and time on ESL monotherapy were both >5 years. Median reduction in SSF from baseline was 66.4% in the full ITT population and 78.3% in the actual monotherapy subgroup; responder (≥50% reduction in SSF) rates were 62.4% and 74.3%, respectively. QOLIE-31 scores increased from baseline in the full ITT population and the actual monotherapy subgroup (4.1- and 7.5-point increases, respectively). MADRS scores decreased from baseline in both the full ITT population and the actual monotherapy subgroup (0.7- and 2.9-point decreases, respectively). TEAEs occurred in 85.4% of patients in the full ITT population and 81.4% of patients in the actual monotherapy subgroup. Incidences of SAEs and TEAEs leading to discontinuation, as well as dizziness, depression, fall, partial seizures with secondary generalization, and complex partial seizures, were higher in the full ITT population than in the actual monotherapy subgroup. Allergic reactions, hyponatremia, and hypothyroidism were infrequent, particularly in the actual monotherapy subgroup. CONCLUSIONS: The results of this post-hoc analysis suggest that long-term treatment with ESL was effective and well tolerated, both as a monotherapy and in combination with other AEDs for FS. QoL and tolerability appeared to be better, and incidence of depression lower, in the patient population taking ESL as a monotherapy, compared with the population that included patients taking ESL as an adjunctive therapy.

The relative roles of power, linear endovenous energy density, and pullback velocity in determining short-term success after endovenous laser ablation of the truncal saphenous veins.

OBJECTIVE: The objective of this study was to describe the relative contributions of power output, linear endovenous energy density (LEED), and pullback rate (PBR) in determining successful long-term occlusion of the truncal saphenous veins after endovenous laser ablation (EVLA). METHODS: A consecutive 203 patients (336 ablated veins) with reflux of the great saphenous vein or small saphenous vein (Clinical, Etiology, Anatomy, and Pathophysiology class C2-C6) defined by duplex ultrasound and clinical criteria were treated with 1470-nm EVLA at a power of 6 to 12 W. Prospective outcomes were evaluated in serial clinical and duplex ultrasound follow-up. Univariate logistic regression (ULR) and multivariable logistic regression modeling assessed LEED, power output, and PBR as success predictors and optimal settings for sustained closure. RESULTS: Higher power outputs (8-12 W) were significantly better than lower outputs (6-7 W) for successful closure. ULR suggested a ≥90% probability of success for power output >10.34 W (P < .001) and LEED >26.56 J/cm (P = .001). Power output was foremost (P < .001) and LEED second (P < .001), and PBR was insignificant overall (P = .38), becoming significant only at LEED values >26 J/cm (P < .001). Multivariable logistic regression confirmed both power (P < .040) and LEED (P < .008) but not PBR (P = .69) as significant determinants. Clinical side effects were not associated by ULR with power output (P = .14), LEED (P = .71), or PBR (P = .39). CONCLUSIONS: Power and LEED are separate but important determinants of short-term EVLA success. Threshold-dependent effects are observed for PBR (LEED ≤26 J/cm or ≥26 J/cm), with significant PBR correlation seen only at higher LEED values. Whereas ideal values for power and LEED differ according to the clinical scenario, our findings suggest that use of higher power outputs and greater LEED values (≥90% success probability achieved with power >10.34 W or LEED >26.56 J/cm) may yield optimal results.

The 2ß Splice Variation Alters the Structure and Function of the Stromal Interaction Molecule Coiled-Coil Domains.

Stromal interaction molecule (STIM)-1 and -2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels after oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil (CC) domains couple to PM Orai1 proteins and gate these Ca2+ release-activated Ca2+ (CRAC) channels, which facilitate store-operated Ca2+ entry (SOCE). Unlike STIM1 and STIM2, which are SOCE activators, the STIM2ß splice variant contains an 8-residue insert located within the conserved CCs which inhibits SOCE. It remains unclear if the 2ß insert further depotentiates weak STIM2 coupling to Orai1 or independently causes structural perturbations which prevent SOCE. Here, we use far-UV circular dichroism, light scattering, exposed hydrophobicity analysis, solution small angle X-ray scattering, and a chimeric STIM1/STIM2ß functional assessment to provide insights into the molecular mechanism by which the 2ß insert precludes SOCE activation. We find that the 2ß insert reduces the overall α-helicity and enhances the exposed hydrophobicity of the STIM2 CC domains in the absence of a global conformational change. Remarkably, incorporation of the 2ß insert into the STIM1 context not only affects the secondary structure and hydrophobicity as observed for STIM2, but also eliminates the more robust SOCE response mediated by STIM1. Collectively, our data show that the 2ß insert directly precludes Orai1 channel activation by inducing structural perturbations in the STIM CC region.

Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials.

OBJECTIVE: In the absence of randomized clinical trials (RCTs) assessing the relative efficacy of antiepileptic drugs (AEDs), meta-analyses are useful resources for informing treatment choices. This meta-analysis assesses the relative efficacy and tolerability of AEDs for adjunctive treatment of refractory partial onset seizures (POS). METHODS: A systematic literature review was conducted to identify pivotal AED trials serving as the basis for US Food and Drug Administration (FDA) approval. INCLUSION CRITERIA: 1) double-blind, placebo-controlled, parallel-group design, with 8- to 14-week maintenance period; 2) enrolled patients ≥16years with refractory POS, including complex partial seizures; 3) study was conducted between 1993 and 2013; and; 4) patients received FDA-approved dosage. Outcomes analyzed: 1) 50% responder rate (≥50% reduction from baseline in seizure frequency); 2) seizure freedom (proportion of seizure-free patients); and 3) discontinuation due to adverse events (AEs). DerSimonian and Laird random-effects model was used to derive odds ratios (OR) and 95% confidence intervals (CI). RESULTS: A total of 29 publications for 11 AEDs (eslicarbazepine, ezogabine, gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide) were included in the meta-analysis. Tiagabine 56mg/day (OR 8.82, 95% CI: 2.77-28.11), pregabalin 600mg/day (OR 8.08, 95% CI: 5.45-11.98), and vigabatrin 3000mg/day (OR 6.23, 95% CI: 1.46-26.20) had the highest OR versus placebo of 50% response. The odds of seizure freedom were ≥7 times greater than placebo for levetiracetam 3000mg/day (OR 11.00, 95% CI: 2.08-58.06), vigabatrin 3000mg/day (OR 7.41, 95% CI: 1.31-41.84), and ezogabine 1200mg/day (OR 7.09, 95% CI: 0.36-58.06). Patients were more likely to discontinue any AED (except low-dose pregabalin) than placebo. CONCLUSION: In this meta-analysis of >9000 patients, those treated with AEDs were more likely than placebo to achieve seizure response or freedom. Patients receiving pregabalin, tiagabine, and vigabatrin had the highest odds of ≥50% reduction in seizures, and patients receiving ezogabine, levetiracetam, and vigabatrin had the highest odds of seizure freedom.

Optimizing clobazam treatment in patients with Lennox-Gastaut syndrome.

Given the complexities managing Lennox-Gastaut syndrome (LGS)-comorbid conditions, multiple associated seizure types that tend to be refractory to treatment-dosage optimization of antiepileptic drug (AED) treatment is a challenge. In the absence of clinical trial data on optimization of AED dosage in patients with LGS, dose titration is guided by personal experience, anecdotal evidence, and specific patient factors (age, comorbid conditions and medications, seizure types, etc.). The goal of this study was to determine whether a 20% increase in adjunctive clobazam was a reasonable benchmark for improved seizure response in patients with LGS who had responded to adjunctive clobazam treatment during a 12-week lead-in trial. This was a post hoc analysis of data from a long-term, open-label extension (OLE) study, which comprised patients who completed 1 of 2 pivotal clobazam lead-in studies. During the lead-in studies, patients received either placebo or clobazam (0.25, 0.50, or 1.0mg/kg/d) (maximum 40mg/d); during OLE, patients received clobazam up to 2.0mg/kg/d (maximum 80mg/d). The post hoc analysis population comprised patients who had ≥25%, ≥50%, or ≥75% seizure reduction from baseline during lead-in clobazam treatment and ≥12months of follow-up data during OLE. Successful dosage increase (i.e., dosage optimization) was defined as ≥20% clobazam dosage increase from OLE baseline, and improved seizure control from OLE baseline (improvement in seizure responder status, or >50% reduction in total seizure frequency). Patients were stratified by responder status after lead-in treatment (OLE baseline) and by lead-in clobazam dosage received. The findings of the analysis indicated that clobazam dosage increases of ≥20% during long-term treatment improved seizure control >80% of patients with LGS who responded to clobazam during lead-in treatment. Rates of successful dosage increase during OLE were high regardless of lead-in dosage received, with the highest rate of successful dosage increase among patients who received low-dosage clobazam during lead-in. Similarly, rates of successful dose increase were high regardless of lead-in seizure responder category, with the highest rates occurring in patients with the highest (≥75%) lead-in response.

Targeting Cysteine Thiols for in Vitro Site-specific Glycosylation of Recombinant Proteins.

Stromal interaction molecule-1 (STIM1) is a type-I transmembrane protein located on the endoplasmic reticulum (ER) and plasma membranes (PM). ER-resident STIM1 regulates the activity of PM Orai1 channels in a process known as store operated calcium (Ca2+) entry which is the principal Ca2+ signaling process that drives the immune response. STIM1 undergoes post-translational N-glycosylation at two luminal Asn sites within the Ca2+ sensing domain of the molecule. However, the biochemical, biophysical, and structure biological effects of N-glycosylated STIM1 were poorly understood until recently due to an inability to readily obtain high levels of homogeneous N-glycosylated protein. Here, we describe the implementation of an in vitro chemical approach which attaches glucose moieties to specific protein sites applicable to understanding the underlying effects of N-glycosylation on protein structure and mechanism. Using solution nuclear magnetic resonance spectroscopy we assess both efficiency of the modification as well as the structural consequences of the glucose attachment with a single sample. This approach can readily be adapted to study the myriad glycosylated proteins found in nature.

Perampanel with concomitant levetiracetam and topiramate: Post hoc analysis of adverse events related to hostility and aggression.

In 4 Phase III registration trials (3 in patients with partial seizures, N=1480; 1 in patients with PGTCS, N=163), perampanel administered to patients already receiving 1-3 concomitant antiepileptic drugs (AEDs) demonstrated statistically superior efficacy compared to placebo in reducing seizure frequency. However, use of perampanel in these studies was associated with a risk of psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation and threats. The present study is a post hoc analysis of pooled data from these 4 trials to determine if concomitant treatment with levetiracetam and/or topiramate increased the risk of hostility- and aggression-related AEs. Treatment-emergent AEs (TEAEs) were determined using a "Narrow & Broad" search based on the Medical Dictionary for Regulatory Activities (MedDRA) standard MedDRA query (SMQ) for hostility- and aggression-related events. The rate of hostility- and aggression-related TEAEs was observed to be similar among perampanel-treated patients: a) receiving levetiracetam (N=340) compared to those not receiving levetiracetam (N=779); b) receiving topiramate (N=223) compared to those not receiving topiramate (N=896); and c) receiving both levetiracetam and topiramate (N=47) compared to those not receiving levetiracetam and topiramate (N=1072). Severe and serious TEAEs related to hostility and aggression were rare and occurred at a similar rate regardless of concomitant levetiracetam and/or topiramate therapy. Taken together, these results suggest that concomitant treatment with levetiracetam and/or topiramate has no appreciable effect on the occurrence of hostility- or aggression-related TEAEs in patients receiving perampanel.

Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV does not preclude the use of BRV in patients with epilepsy.