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Stephane Borentain,1 David Williamson,2,3 Ibrahim Turkoz,4 Vanina Popova,5 William V McCall,3 Maju Mathews,1 Frank Wiegand1 1Department of Global Medical Affairs, Janssen Research & Development, LLC, Titusville, NJ, USA; 2CNS Scientific Affairs Liaisons, Janssen Scientific Affairs, LLC, Titusville, NJ, USA; 3Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA; 4Department of Clinical Statistics, Janssen Research & Development, LLC, Titusville, NJ, USA; 5Department of Neuroscience Clinical Development, Janssen Research & Development, Beerse, BelgiumCorrespondence: Stephane BorentainDepartment of Global Medical Affairs, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USATel +1 609-7304420Email SBorent1@ITS.JNJ.comPurpose: To evaluate the relationship of sleep disturbance to the antidepressant effects of esketamine.Materials and Methods: Two double-blind, 4-week studies randomized adults with treatment-resistant depression (TRD) to placebo or esketamine nasal spray, each with newly initiated antidepressant. Sleep was assessed using Montgomery–Åsberg Depression Rating Scale (MADRS) item 4. Change in response (≥ 50% decrease in MADRS total score) and remission (total MADRS score ≤ 12) at day 28 was examined by presence/absence of baseline sleep disturbance using logistic regression models. Impact on reported sleep disturbance (MADRS item 4 score) was examined using ANCOVA models.Results: At baseline, most patients reported disturbed sleep – moderate/severe (65.3%, 369/565), mild (25.3%, 143/565), or none/slightly (9.4%, 53/565) – with similar distribution between treatment groups. A higher proportion of esketamine-treated patients achieved response (OR = 2.05; 95% CI: 1.40– 3.02; P < 0.001) and remission (OR = 1.81; 95% CI: 1.23– 2.66; P = 0.003) at day 28 compared to antidepressant plus placebo, regardless of presence/severity of sleep disturbance. Consistent with this, sleep (MADRS item 4 score) improved in both groups after the first dose, more so with esketamine by day 8 (between-group difference: P ≤ 0.02 at all time points). Across both treatment groups, 1-point improvement in sleep at day 8 increased the probability of antidepressant response on day 28 by 26% (OR = 1.26, 95% CI: 1.12– 1.42; P < 0.001), and remission by 28% (OR = 1.28, 95% CI: 1.14– 1.43; P < 0.001).Conclusion: Antidepressant efficacy of esketamine was demonstrated in patients with TRD, regardless of the presence of sleep disturbance. After 8 days of treatment and thereafter, significantly more esketamine-treated patients reported improvement in sleep versus antidepressant plus placebo.Keywords: esketamine, treatment-resistant depression, sleep disturbance, insomnia

Background Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. Methods This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression–Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. Results Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. Conclusions These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. Trial Registration ClinicalTrials.gov identifier: NCT02497287

Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore, we outline the characteristics and skills that enable physicians to have a successful career in pharma.

Background Major depressive disorders (MDDs) including treatment-resistant depression (TRD) are common disabling conditions, but data on their epidemiology in Japan are limited. This study investigated the incidence, epidemiology, and direct medical costs of TRD and pharmaceutically-treated depression (PTD) in Japan to increase our health economic understanding of this phenotype of MDD. Methods A retrospective cohort study from a private health insurance claims database estimated the 1-year incidence of PTD and TRD and described the health services used and direct medical costs associated with these conditions. Results In the year from 1 April 2012 through 31 March 2013, we identified 1143 incident PTD cases among 98,552 eligible subjects, i.e. 11.59 cases/1000 patient-years. Of the PTD patients, 51.4% were women. Within the 1-year observation interval 137 patients failed more than two antidepressive treatment approaches and thus developed TRD. Though co-morbid conditions and age were similar among PTD and TRD patients, medical costs per patient (patient-year) during their treatment intervals were 1.01 million JPY (0. 540 million JPY) in the TRD population and 0.643 JPY million JPY (0.645 million JPY) in the PTD population who did not convert into TRD. Conclusions This study describes the PTD and TRD patient populations in a large claims database in Japan and highlights an unmet medical need for the treatment of TRD to provide better preventative measures and interventions for the treatment of depression. Electronic supplementary material The online version of this article (10.1007/s40801-017-0126-5) contains supplementary material, which is available to authorized users.

BACKGROUND: The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). METHODS: This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. RESULTS: Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 (3.00) and -16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (-3.8 [2.97]). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. CONCLUSIONS: A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-minute IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy. ispartof: Biological Psychiatry vol:80 issue:6 pages:424-431 ispartof: location:United States status: published

International audience; Die Kernaufgabe der Projektgruppe des DWDS besteht darin, den in den Korpora enthaltenen Wortschatz lexikographisch und korpusbasiert zu beschreiben. Es erschien uns aber von Beginn des Projekts an sinnvoll, die Daten, die die Basis dieser lexikographischen Arbeiten bilden, auch allgemein der empirischen linguistischen Forschung zum Deutschen in Geschichte und Gegenwart zur Verfügung zu stellen. Durch den Zugriff auf die durch rechtliche Vereinbarungen geklärten Teile der Wörterbuchbasis ist es somit den Benutzerinnen und Benutzern unseres Wörterbuchs jederzeit möglich, die lexikographischen Angaben in unserem Wörterbuch zu prüfen, aber auch eigene korpusbasierte Recherchen auf den verschiedenen Korpora des DWDS durchzuführen.

We present a global sensitivity analysis methodology for drawing inference about the mean at the final scheduled visit in a repeated measures study with informative dropout. We review and critique the sensitivity frameworks developed by Rotnitzky et al. and Daniels and Hogan. We identify strengths and weaknesses of these approaches and propose an alternative. We illustrate our approach via a comprehensive analysis of the RIS-INT-3 trial.

Adverse cognitive effects are an important concern for drugs that influence the central nervous system. Carisbamate is a novel drug in development for treatment of seizures and neuropathic pain. Information on its cognitive effects is limited. Three controlled, multiple-dose, crossover studies with treatment durations of 5-9 days were designed to examine the cognitive effects of carisbamate on healthy volunteers. In one study, apparent dose-dependent effects on response, vigilance, and recognition speed were observed (1000 mg and 1500 mg/day). Carisbamate did not differ from placebo for most variables in the other two studies, but increased reaction time and reduced Sternberg memory were seen at higher dosages. Carisbamate did not produce clinically significant adverse effects on cognitive performance at doses1000 mg/day. Effects were mild to modest at the higher doses tested.

Summary Purpose: To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy. Methods: Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure. Results: At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047). Conclusion: This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double-blind, cross-over, placebo-controlled study of essential tremor. Sixty-two patients (intent-to-treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21-day treatment periods. The Fahn-Tolosa-Marin Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo. © 2010 Movement Disorder Society

This 24-week, multicenter, open-label trial was designed to evaluate the dosing, effectiveness, and safety of topiramate monotherapy for epilepsy and to identify patient and clinical characteristics predictive of optimally effective stabilized monotherapy doses. Of 406 randomized patients, 244 comprised the evaluable-for-efficacy population (12 weeks of treatment and stabilized topiramate dose during final 28 days); 213 were on topiramate monotherapy at the end of the trial. The mean stabilized daily dose of topiramate over the last 28 days of treatment (primary endpoint) was significantly lower for patients reporting one to three seizures (low seizure frequency, n=147) than for those reporting more than three seizures (high seizure frequency, n=66) during a 3-month retrospective baseline period (191 mg vs 239 mg, P=0.003). Patients in the low-seizure-frequency group reached a stable topiramate dose after a median of 36 days, compared with 53 days for patients in the high-seizure-frequency group. Linear and stepwise regression analyses showed baseline seizure frequency and lifetime seizure count to be significant (P0.05) predictors of the stabilized dosage. Most treatment-emergent adverse events (TEAEs) were mild to moderate; those occurring with cumulative incidence rates10% in either seizure frequency group were paresthesia, fatigue, anorexia, dizziness, somnolence, headache, and hypoesthesia; 18.2% of patients discontinued topiramate because of a TEAE, 5.1% reported serious TEAEs, and no deaths were reported during the study.

Objectives: The purposes of this review were toassess the efficacy of topiramate as monotherapy for epilepsy and migraine prevention, describe how it should be used, and give clinical advice on how to manage the practical aspects of dosing, titration, and possible adverse events in these 2 indications. Methods: We searched the PubMed and BIOSIS databases using the key words topiramate, epilepsy, and migraine from the year 1987 onward, and subsequently focused the search on larger controlled trial studies of topiramate as monotherapy. Results: Studies have evaluated the use of topiramateas monotherapy in the treatment of partial-onset and generalized seizures and in the prevention of migraine. In a randomized study, 75% of epilepsy patients treated with 400 mg/d topiramate remained seizure free at 1 year. Patients in the same study treated with a lower dose of topiramate (50 mg/d) also experienced notable seizure reductions, with 59% of patients free of seizures at 1 year. A comparison trial of topiramate (100 or 200 mg/d), valproate, and carbamazepine found that topiramate was associated with a similar time to first posttreatment seizure as the other 2 agents (P = NS). Trials of topiramate monotherapy in migraine prevention found that 100 mg/d was associated with a ≥50% reduction in monthly migraine frequency in 49% to 54% of patients. The migraine prevention trials typically used a starting dose of 25 mg/d, with weekly increases of 25 mg and an initial monotherapy target dose of 100 mg/d. The most common adverse events associated with topiramate are paresthesia, weight loss, and other centrally mediated symptoms, many of which may be ameliorated by proper titration and dosing and by good communication between physician and patient. Conclusions: Data from controlled trials suggest that 100 mg/d topiramate as monotherapy is effective in the treatment of partial-onset and generalized seizures and in the prevention of migraine.

The authors investigated the time course of leukocyte infiltration compared with microglial activation in adult rat brain slices after permanent middle cerebral artery occlusion (MCAO). To distinguish peripheral leukocytes from microglia, the blood cells were prelabeled in vivo with Rhodamine 6G (Rhod6G) IV before induction of ischemia. At specific times after infarct, invading leukocytes, microglia, and endothelial cells were labeled in situ with isolectin (IL)B4-FITC (ILB4). Six hours after MCAO only a few of the ILB4+ cells were colabeled by Rhod6G. These cells expressed the voltage-gated inwardly and outwardly rectifying K+ currents characteristic of macrophages. The majority of the ILB4+ cells were Rhod6G− and expressed a lack of voltage-gated channels, recently described for ramified microglial cells in brain slices, or exhibited only an inward rectifier current, a unique marker for cultured (but unstimulated) microglia. Forty-eight hours after MCAO, all blood-borne and the majority of Rhod6G− cells expressed outward and inward currents indicating that the intrinsic microglial population exhibited physiologic features of stimulated, cultured microglia. The ILB4+/Rhod6G− intrinsic microglial population was more abundant in the border zone of the infarct and their morphology changed from radial to ameboid. Within this zone, the authors observed rapidly migrating cells and recorded this movement by time-lapse microscopy. The current findings indicate that microglial cells acquire physiologic features of leukocytes at a later time point after MCAO.

SV129 or C57BL/6 mice were exposed to hyperbaric oxygenation (HBO, 5 days, 1 h every day, 100% O(2) at 3 atm absolute). One day after the 5th HBO session focal cerebral ischemia was induced. In SV129 mice, HBO induced tolerance against permanent focal cerebral ischemia (n=42, mean infarct volume reduction 27%, P=0.001), but not against transient (30 or 60 min) focal cerebral ischemia. In the C57BL/6 strain of mice, HBO did not induce tolerance against focal cerebral ischemia, even when the duration of ischemia or the HBO protocol were modified. For the first time we demonstrate that HBO can induce tolerance to focal cerebral ischemia, but this effect is strain dependent.

Objective. To compare placebo responses in neuropathic pain syndromes. Design. Systematic literature review and meta-analysis. Setting and Patients. Randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with ≥5 days follow-up. Interventions. Placebo response. Outcome Measures. Pain intensity and responder rates (proportion reporting ≥50% pain relief). Meta-regression models were built. Results. Ninety-four studies (N = 5,317) were included in the pain intensity analysis; 47 studies (N = 3,087) were included in the responder analysis. After controlling for potential confounders (e.g., subject characteristics, study design characteristics), the placebo response was found to be large and varied with the pain syndrome. Compared with diabetic neuropathic/polyneuropathic pain (DPN), the placebo response for a decline in pain intensity and responder rate was smaller in trials that assessed central pain and postherpetic neuralgia (PHN) and larger in trials that assessed HIV pain. The model-predicted mean decrease (95% confidence interval [CI]) from baseline in pain intensity (0–10 scale) was as follows: DPN, 1.45 (1.35 to 1.55); PHN, 1.16 (1.03 to 1.29); central pain, 0.44 (−0.41 to 1.30); HIV pain, 1.82 (1.51 to 2.12). The predicted responder rates (95% CI) were as follows: DPN, 20% (14.6 to 25.8); PHN, 11.5% (8.4 to 14.5); central pain, 7.2% (2.1 to 12.3); HIV pain, 42.8% (34.9 to 50.7). The type of treatment in the active arm also influenced the placebo response. Conclusions. Placebo response is influenced by the pain syndrome evaluated. These differences should be considered when evaluating novel compounds for the treatment of neuropathic pain conditions.

Placebo and pharmacodynamic (PD) models were developed which link temporal measures of efficacy in children with attention deficit hyperactivity disorder (ADHD) and methylphenidate (MPH) plasma concentrations from adults. These models can be used to predict daily pediatric clinical measure profiles following administration of different MPH formulations in children without conducting pediatric pharmacokinetic (PK) or PD studies by using more easily obtained adult PK data. Mean PK data from various extended-release MPH formulations studied in adults and mean PD data from nine pediatric efficacy studies were obtained from the literature. The individual time-course of the clinical measures from three pediatric trials were also analyzed after being combined with the meta-analysis data. The clinical measure profiles following placebo administration were described by indirect response models with time-varying elimination rates. MPH pharmacodynamic effect was described by E(max) models, which included time-dependent tolerance. Internal and external evaluations using a visual predictive check technique confirmed the prediction capability of the models. This modeling exercise demonstrated that time courses of MPH concentrations in adults with different drug release patterns can be used to predict time courses of clinical efficacy parameters in pediatrics by employing the models developed by meta-analysis.

To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy.Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure.At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047).This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Approved symptomatic therapies for Alzheimer's disease (AD) provide modest relief. In the future, it is likely that symptomatic treatments will be utilized with AD modifying therapies, the development of which are currently a primary focus of research. The nicotinic α7 receptor agonist may be an attractive drug candidate to potentially improve cognition in Alzheimer's disease patients either as a stand-alone therapy or in combination with other symptomatic treatments. EVP-6124 is a novel, potent, and selective α7 nicotinic receptor agonist. EVP-6124 has an excellent brain to plasma exposure ratio and has shown excellent efficacy and potency in a number of animal models of cognition. Four clinical studies in >125 healthy normal human subjects have been completed with EVP-6124, including a single-ascending-dose study, a 14-day multiple-ascending-dose study, a 21-day multiple-dose study, and a single-dose relative bioavailability, food, and gender effect study. EVP-6124 exhibited linear kinetics over the range of 1 to 180 mg and demonstrated a half-life suitable for once daily dosing. EVP-6124 appears to be safe and well tolerated for up to 21 days as measured by adverse events, vital signs, continuous cardiac monitoring, physical examination, and clinical laboratory evaluations. In addition, in normal volunteers, EVP-6124 demonstrated pro-cognitive effects (CogState testing) in various cognitive domains including executive function. These data suggest that EVP-6124 administered to AD subjects on stable cholinesterase inhibitor therapies may have potential benefit and that further study in this patient population is indicated. Larger phase II studies are currently being initiated in both Alzheimer's disease and schizophrenia.

The efficacy and safety of carisbamate, an investigational neuromodulator currently in development for epilepsy, were examined in a multicenter, randomized, double-blind, cross-over, placebo-controlled study of essential tremor. Sixty-two patients (intent-to-treat analysis set; mean age 64 years; 66% men) received carisbamate 400 mg/day or matching placebo in a crossover study design with two 21-day treatment periods. The Fahn-Tolosa-Marín Tremor Rating Scale (TRS) was the primary assessment tool. Carisbamate and placebo treatment did not differ in their effect on the TRS (P = 0.94) or on measures of affect, mood, or quality of life. Carisbamate was generally well tolerated and had an adverse event profile comparable to that of placebo.

Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being.In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy.Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P.001), all liver enzyme levels (P.01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P.001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P.001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P.05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo.Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.

The role of tissue-type plasminogen activator (rt-PA) during thromboly­sis of stroke is poorly understood. Recently, a direct neurotoxic effect of rt-PA was reported. This is at odds with studies that show an improved outcome. Here we inves­tigated the effect of rt-PA after failure to recanalize the occluded brain vessel. Sprague­Dawley rats underwent thromboembolic stroke. They were assigned to four groups according to the patency of the middle cerebral artery on cerebral x-ray angiography after treatment with saline or rt-PA (15 mg/kg body weight over 90 min, starting 1 h after embolization): (1) control without recanalization (n = 5), (2) rt-PA treatment without recanalization (n = 5), (3) control with spontaneous recanalization (n = 2), and (4) rt-PA treatment with recanalization (n = 3). Six sets of diffusion-and perfusion-weighted (bolus-track) magnetic resonance images were acquired throughout the 6-h observation period. When recanalization was successful, rt-PA sig­nificantly improved perfusion values and the final infarct size. However, final infarct volumes in nonrecanalized rt-PA-treated animals compared to control animals were 67.4% ± 5.4% versus 47.7% ± 17.9% of the ipsilateral hemisphere (P = 0.042) at corresponding perfusion values. Our results suggest that rt-PA treatment worsens outcome in a model of thromboembolic stroke if recanalization is not successful.

Introduction International guidelines recommend assessing the overall long-term benefit of antiepileptic drugs (AEDs) using multidimensional measures. Effectiveness encompasses the effects of a product's efficacy, safety, and tolerability. Retention reflects effectiveness over time. This double-blind study (NCT00563459) was designed to compare the 6- and 12-month retention (as the primary parameter) of patients taking carisbamate (the investigational drug), topiramate, and levetiracetam when used as adjunctive treatment for partial onset seizures (POS). The retention hypotheses were that carisbamate would be at least as good as each comparator. Additionally, because cognitive and neuropsychiatric adverse events (AEs) have an impact on acceptance of therapy, the incidences of these AEs were assessed with the hypotheses that carisbamate would be superior to topiramate on cognitive AEs and superior to levetiracetam on neuropsychiatric AEs. The aforementioned hypotheses were analyzed using a fixed-sequence testing procedure. Methods Following a screening phase, ∼600 adult patients with POS and a history of inadequate response to treatment with e1AED had to be randomized in a 1:1:1 ratio to enter a 7-week titration period. Target daily doses of study medications were carisbamate 800 mg/day, topiramate 300 mg/day or levetiracetam 2000 mg/day, (dose adjustment could be done within the limits of 400–1200 mg/day; 200–400 mg/day; or 1000–3000 mg/day, respectively). After titration, patients entered the 17-week maintenance period. The 7-week titration and 17-week maintenance phases comprise the 6-month (24-week) core double-blind phase, with an option for an additional 6-month double-blind extension phase. The primary endpoint was the time from the first intake of study medication to any cause of discontinuation over the 6-month core double-blind phase. Cognitive AEs, neuropsychiatric AEs, reasons for discontinuation, seizure rates, cognitive changes relative to baseline assessed with a computerized cognitive test battery, and patient-reported mood states, behavioral, and cognitive changes relative to baseline using the Profiles of Mood Status questionnaire, Center for Epidemiologic Studies Depression Scale, and patient- and observer-reported Overall Mental Effects Questionnaire among the 3 treatment arms were assessed at 6- and 12-months post-randomization. This study design can provide unique information and meaningful data that might be valuable for clinical decision-making. Support Support was provided by Johnson & Johnson Pharmaceutical Research & Development , LLC.

We studied the effect of dihydralazine treatment of hypertension in spontaneously hypertensive stroke-prone rats in a model of permanent focal cerebral ischemia (stroke). After occlusion of the middle cerebral artery systemic arterial pressure (SAP) was lowered with a computer controlled infusion device from 163 to 135 or 117 mm Hg for 24h. In the control group SAP was not manipulated. Reduction of SAP to normotension (117 mm Hg) significantly worsened outcome and increased infarct volume measured 7 days after induction of ischemia, whereas a mild reduction of SAP (to 137 mm Hg) had no statistically significant effect on outcome or infarct volume. We conclude that pharmacological treatment of hypertension may negatively affect neurological outcome and infarct volume in a rat stroke model.

The authors show that the inhibitor of the succinate dehydrogenase, 3-nitroproprionic acid (3-NPA), which in high doses and with chronic administration is a neurotoxin, can induce profound tolerance to focal cerebral ischemia in the rat when administered in a single dose (20 mg/kg) 3 days before ischemia. Infarcts were approximately 70% and 35% smaller in the 3-NPA preconditioned groups of permanent and transient focal cerebral ischemia, respectively. This regimen of 3-NPA preconditioning neither induced necrosis, apoptosis, or any other histologically detectable damage to the brain, nor did it affect behavior of the animals. 3-NPA led to an immediate (1-hour) and long-lasting (3-day) decrease in succinate dehydrogenase activity (30% reduction) throughout the brain, whereas only a short metabolic impairment occurred (ATP decrease of 35% within 30 minutes, recovery within 2 hours). The authors found that 3-NPA induces a burst of reactive oxygen species and the free radical scavenger dimethylthiourea, when administered shortly before the 3-NPA stimulus, completely blocked preconditioning. Inhibition of protein synthesis with cycloheximide given at the time of 3-NPA administration completely inhibited preconditioning. The authors were unsuccessful in showing upregulation of mRNA for the manganese superoxide dismutase, and did not detect increased activities of the copper-zinc and manganese superoxide dismutases, prototypical oxygen free radicals scavenging enzymes, after 3-NPA preconditioning. The authors conclude that it is possible to pharmacologically precondition the brain against focal cerebral ischemia, a strategy that may in principal have clinical relevance. The data show the relevance of protein synthesis for tolerance, and suggests that oxygen free radicals may be critical signals in preconditioning.

The mechanisms by which a sublethal preconditioning stress increases the resistance of the brain to a subsequent ischaemic event are not fully elucidated. This phenomenon seems to involve the neo-synthesis of proteins, but little is known about the signalling cascade and the nature of the protective proteins that are involved. Two experimental paradigms were used to induce tolerance to focal cerebral ischaemia achieved by middle cerebral-artery occlusion in the rat: first, metabolic inhibition by a single dose of 3-nitropropionic acid (NPA), an inhibitor of the succinate dehydrogenase, was induced 3 days before transient focal cerebral ischaemia (90 min); second, hyperbaric oxygenation (1 h, 100% oxygen at 2 atm) was performed daily for the 5 days preceding permanent focal cerebral ischaemia. Neither stimuli caused any detectable brain damage. The 3-NPA pretreatment, and 2 atm hyperbaric oxygen (HBO) pre-exposition led to infarct volumes, which were smaller than in control animals by approximately 30%. Both preconditioning stimuli induced the generation of oxygen free radicals (OFR) as measured by chemiluminescence in the 3-NPA group, and malondialdehyde (MDA) production in the HBO group. Furthermore, tolerance induction was abolished in both groups when animals were pretreated with the free-radical scavenger, dimethylthiourea (DMTU). These data argue for a critical role of OFRs in tolerance induction by metabolic inhibition or HBO. Since most of the known preconditioning stimuli lead to OFRs, we forward the hypothesis that OFRs may constitute a common signal, triggering the induction of tolerance to ischaemia. This hypothesis is further supported by the effects of free radicals on transcription factors, such as nuclear factor (NF)-B. Their possible interaction in tolerance, as well as the nature of the putative neuroprotective proteins, will be discussed. Hyperbaric oxygenation seems to be a useful and safe way to induce tolerance to focal cerebral ischaemia, which may lead to clinical applications.

ContextHypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of γ-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system.ObjectiveTo determine if topiramate is a safe and efficacious treatment for alcohol dependence.Design, Setting, and ParticipantsDouble-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites.InterventionsUp to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.Main Outcome MeasuresPrimary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma γ-glutamyltransferase).ResultsTreating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P

Sublethal ischemia leads to increased tolerance against subsequent prolonged cerebral ischemia in vivo. In the present study we modeled preconditioning mechanisms in a neuronal-enriched culture. Damage was significantly reduced (up to 72%) with 1.5 h of oxygen-glucose deprivation 48–72 h before 3 h oxygen-glucose deprivation. Tolerance was also elicited by Na+-K+-ATPase inhibition. No damage was observed when astroglial or endothelial cells were exposed to hypoxia for 3 and 6 h, respectively. We conclude that hypoxic preconditioning is a robust neuronal phenomenon in vitro with a similar temporal pattern and selective cellular vulnerability as the ischemic tolerance phenomenon shown in vivo.

We applied serial analysis of gene expression (SAGE) to study differentially expressed genes in mouse brain 14 hr after the induction of focal cerebral ischemia. Analysis of >60,000 transcripts revealed 83 upregulated and 94 downregulated transcripts (more than or equal to eightfold). Reproducibility was demonstrated by performing SAGE in duplicate on the same starting material. Metallothionein-II (MT-II) was the most significantly upregulated transcript in the ischemic hemisphere. MT-I and MT-II are assumed to be induced by metals, glucocorticoids, and inflammatory signals in a coordinated manner, yet their function remains elusive. Upregulation of both MT-I and MT-II was confirmed by Northern blotting. MT-I and MT-II mRNA expression increased as early as 2 hr after 2 hr of transient ischemia, with a maximum after 16 hr. Western blotting and immunohistochemistry revealed MT-I/-II upregulation in the ischemic hemisphere, whereas double labeling demonstrated the colocalization of MT with markers for astrocytes as well as for monocytes/macrophages. MT-I- and MT-II-deficient mice developed approximately threefold larger infarcts than wild-type mice and a significantly worse neurological outcome.For the first time we make available a comprehensive data set on brain ischemic gene expression and underscore the important protective role of metallothioneins in ischemic damage of the brain. Our results demonstrate the usefulness of SAGE to screen functionally relevant genes and the power of knock-out models in linking function to expression data generated by high throughput techniques.