Antiepileptic Drug Discovery and Development: What Have We Learned and Where Are We Going?

Current marketed antiepileptic drugs (AEDs) consist of a variety of structural classes with different mechanisms of action. These agents typically have non-overlapping efficacy and side-effect profiles presenting multiple treatment options for the patient population. However, approximately 30% of seizure sufferers fail to respond to current therapies often because poorly tolerated side-effects limit adequate dosing.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹⁰⁷Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder.

Airway response to emotion- and disease-specific films in asthma, blood phobia, and health.

Earlier research found autonomic and airway reactivity in asthma patients when they were exposed to blood-injection-injury (BII) stimuli. We studied oscillatory resistance (R(os)) in asthma and BII phobia during emotional and disease-relevant films and examined whether muscle tension counteracts emotion-induced airway constriction. Fifteen asthma patients, 12 BII phobia patients, and 14 healthy controls viewed one set of negative, positive, neutral, BII-related, and asthma-related films with leg muscle tension and a second set without.

Real-time PMIRRAS studies of in situ growth of C11Eg6OMe on gold and immersion effects.

We studied the growth of self-assembling monolayers of C(11)Eg(6)OMe on gold under aqueous conditions. With the help of polarisation modulation infrared reflection absorption spectroscopy (PMIRRAS) we monitored the evolution of characteristic absorption modes in the fingerprint region (1050-1500 cm(-1)) during the later stages of the growth of the SAM. We observed a change from rather amorphous structure with mixed all-trans and helical conformation to an ordered structure with predominantly helical structure over time.

Dimensional structure of the Social Interaction Anxiety Scale according to the analysis of data obtained with a German version.

The Social Interaction and Anxiety Scale (SIAS) is widely used to assess social interaction anxiety. Yet its dimensional structure is still not well-defined. Especially, the conceptual pertinence of three negatively keyed items has been challenged.

Coincidence of paroxysmal supraventricular tachycardia and panic disorder: two case reports.

Panic disorder (PD) is characterised by sudden attacks of intense fear with somatic symptoms including palpitations and tachycardia. Reciprocally, palpitations caused by paroxysmal supraventricular tachycardia (PSVT) are commonly associated with anxiety and may therefore be misdiagnosed as PD. As demonstrated by two case reports, PSVT and PD can occur comorbidly in a chronological sequence, with PSVT possibly precipitating and maintaining PD via interoceptive processes or, alternatively, with PD increasing the risk for PSVT by elevating stress levels.

Changes in pain-related coping strategies and their importance for treatment outcome following multimodal inpatient treatment: does sex matter?

Unlabelled: While sex differences in pain-related coping have been widely reported, little is known on sex differences in changes in coping following multimodal pain treatment and how these changes relate to treatment outcome. The present prospective study therefore aimed to investigate sex differences in coping strategies between boys and girls with chronic pain prior to multimodal inpatient treatment and at 3-month follow-up. Sixty-four boys and 103 girls with various pain disorders were evaluated.

Investigations of the water clusters of the protected amino acid Ac-Phe-OMe by applying IR/UV double resonance spectroscopy: microsolvation of the backbone.

In order to investigate the influence of hydration on the backbone of a peptide or protected amino acid, the successive aggregation of water to Ac-Phe-OMe is analysed by means of IR/UV double resonance spectroscopy. To achieve meaningful results the spectra have been recorded in the region of the amide A and OH stretching vibrations as well as the amide I/II modes. Comparison with ab initio and DFT calculations leads to size-selective structural assignments.

Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders.

The purpose of the present study was to establish a short paradigm for the examination of classical aversive conditioning processes for application in patients with anxiety disorders. We measured behavioral, autonomic and neural correlates of the paradigm in healthy subjects, applying functional magnetic resonance imaging (fMRI) and measurement of skin conductance. Therefore, neutral visual stimuli were paired with an unpleasant white noise as unconditioned stimulus.

Pricing and availability intervention in vending machines at four bus garages.

Objective: To evaluate the effects of lowering prices and increasing availability on sales of healthy foods and beverages from 33 vending machines in 4 bus garages as part of a multicomponent worksite obesity prevention intervention.

Methods: Availability of healthy items was increased to 50% and prices were lowered at least 10% in the vending machines in two metropolitan bus garages for an 18-month period. Two control garages offered vending choices at usual availability and prices.

Worksite environment intervention to prevent obesity among metropolitan transit workers.

Objective: The results of an 18-month worksite intervention to prevent obesity among metropolitan transit workers are reported.

Methods: Four garages in a major metropolitan area were randomized to intervention or control groups. Data were collected during the fall of 2005 prior to the start of the intervention and during the fall of 2007, after the intervention ended.

Dexmedetomidine-associated bradycardia progressing to pulseless electrical activity: case report and review of the literature.

Dexmedetomidine is an alpha(2)-agonist indicated for sedation in critically ill patients and procedural sedation in nonintubated patients. It is a distinctive sedative because it does not cause respiratory depression, but it may cause hypotension and bradycardia. We describe a 74-year-old man who was receiving dexmedetomidine for agitation and experienced progressive bradycardia.

An updated focused review of dexmedetomidine in adults.

Objective: To evaluate recent comparative studies regarding the safety and efficacy of dexmedetomidine in adults.

Data Sources: Articles evaluating safety and efficacy of dexmedetomidine were identified from an English-language MEDLINE search (1996-July 2009), with a focus on data published since our previous review in 2007 to the present. MeSH terms included dexmedetomidine, medetomidine, alpha2-agonist, and sedation.

Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia.

Cognitive behavioral therapy (CBT) is efficacious for panic disorder with agoraphobia (PD/A). Nevertheless, the active ingredients of treatment and the mechanisms through which CBT achieves its effects remain largely unknown. The mechanisms of action in CBT (MAC) study was established to investigate these questions in 369 patients diagnosed with PD/A.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study.

Introduction: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol.

Role of the substrate in electronic structure, molecular orientation, and morphology of organic thin films: diindenoperylene on rutile TiO2(110).

The results of our multitechnique investigation performed on diindenoperylene thin films deposited on rutile TiO2(110) show island growth, with crystallites nucleating preferentially along the [110] substrate crystallographic axis. The findings evidence that the films' properties at the interface are common to those found for a number of organic molecules deposited on the same substrate, revealing that the structural and morphological properties of organic thin films on rutile TiO2(110) are completely driven by its surface morphology.

Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574).

Human ether-à-go-go-related gene (hERG) potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report the discovery of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole-cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes more than 10-fold with an EC(50) value of 0.

Interoceptive sensitivity in anxiety and anxiety disorders: an overview and integration of neurobiological findings.

Interoceptive sensitivity, particularly regarding heartbeat, has been suggested to play a pivotal role in the pathogenesis of anxiety and anxiety disorders. This review provides an overview of methods which are frequently used to assess heartbeat perception in clinical studies and summarizes presently available results referring to interoceptive sensitivity with respect to heartbeat in anxiety-related traits (anxiety sensitivity, state/trait anxiety), panic disorder and other anxiety disorders. In addition, recent neurobiological studies of neuronal activation correlates of heartbeat perception using positron emission tomography (PET), functional magnetic resonance imaging (fMRI) or electroencephalographic (EEG) techniques are presented.

Evaluation of an evidence-based guidance on the reduction of physical restraints in nursing homes: a cluster-randomised controlled trial [ISRCTN34974819].

Background: Physical restraints are regularly applied in German nursing homes. Their frequency varies substantially between centres. Beneficial effects of physical restraints have not been proven, however, observational studies and case reports suggest various adverse effects.

The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site.

The mammalian KCNQ (Kv7) gene family is composed of five members (KCNQ1-5). KCNQ2, Q4 and Q5 (KCNQ2-5) channels co-express with KCNQ3 to form heterotetrameric voltage-gated K(+) (KCNQ2-5/3) channels that underlie the endogenous M-current and regulate neuronal excitability in CNS and PNS neurons. Openers of one or a mixture of these channels may be an attractive therapeutic agent for epilepsy and pain.

Use of subcutaneous lepirudin in an obese surgical intensive care unit patient with heparin resistance.

Objective: To report the use of subcutaneous lepirudin in an obese patient with heparin resistance.

Case Summary: A 34-year-old morbidly obese male (weight 145 kg) presented with hypoxia on postoperative day 1 following a sigmoid colectomy. A continuous unfractionated heparin infusion was started for a suspected pulmonary embolism.

A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients.

Background: Although no ideal sedative exists, dexmedetomidine is unique because it produces sedation and analgesia without decreasing the respiratory drive. Hemodynamic responses to dexmedetomidine are variable and dependent on the patient population. Our initial experience was associated with an unacceptable incidence of hypotension and bradycardia.

Optical spectra obtained from amorphous films of rubrene: Evidence for predominance of twisted isomer.

In order to investigate the optical properties of rubrene we study the vibronic progression of the first absorption band (lowest pi-->pi( *) transition). We analyze the dielectric function epsilon(2) of rubrene in solution and thin films using the displaced harmonic oscillator model and derive all relevant parameters of the vibronic progression. The findings are supplemented by density functional calculations using B3LYP hybrid functionals.

[The research network PANIC-NET: improving the treatment of panic disorder - from a better understanding of fear circuit mechanisms to more effective psychological treatment and routine care].

Panic disorder with agoraphobia (PD/AG) is one of the most costly and disabling anxiety disorders with a large range of secondary mental health problems. According to numerous clinical trials, cognitive-behavioural therapy (CBT) represents the most effective psychotherapeutic intervention for PD/AG. Little is known about the exact mechanisms of CBT and their neurobiological effects on the fear network.

The impact of visual flow stimulation on anxiety, dizziness, and body sway in individuals with and without fear of heights.

Individuals with acrophobia experience anxiety and dizziness when exposed to heights. It may be that their balance system is disturbed and that they therefore have to rely more strongly on visual information. We tested this hypothesis by exposing 20 individuals with high fear of heights and 20 healthy control participants to nine different visual flow stimuli through a head mounted display, thereby inducing a conflict between visual input and somatosensory information.