Amisulpride augmentation in clozapine-unresponsive schizophrenia: A double-blind, placebo-controlled, randomised trial of clinical and cost-effectiveness.

BACKGROUND: When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. OBJECTIVES: The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. DESIGN: The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. SETTINGS: The study was set in NHS multidisciplinary teams in adult psychiatry. PARTICIPANTS: Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. INTERVENTIONS: Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. RESULTS: A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. LIMITATIONS: The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. CONCLUSIONS: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. TRIAL REGISTRATION: EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information

Higher borides and oxygen-enriched Mg-B-O inclusions as possible pinning centers in nanostructural magnesium diboride and the influence of additives on their formation

The study of high pressure (2 GPa) synthesized MgB2-based materials allows us to conclude that higher borides (with near MgB12 stoichiometry) and oxygen-enriched Mg-B-O inclusions can be pinning centers in nanostructural magnesium diboride matrix (with average grain sizes of 15-37 nm). It has been established that additions of Ti or SiC as well as manufacturing temperature can affect the size, amount and distribution of these inclusions in the material structure and thus, influence critical current density. The superconducting behavior of materials with near MgB12 stoichiometry of matrix is discussed.Comment: 4 pages, 1 figues, presented at VORTEX VI-2009, accepted for Physica

Percutaneous coronary intervention in Europe 1992-2003

peer reviewedAims: The purpose of this registry is to collect data on trends in interventional cardiology within Europe. Special interest focuses on relative increases and ratios in newer revascularization approaches and its distribution in different regions in Europe. We report the data of the year 2003 and give an overview of the development of coronary interventions since 1992, when the first data collection was performed. Methods and results: Questionnaires were distributed yearly to delegates of all national societies of cardiology represented in the European Society of Cardiology to collect the case numbers of all local institutions and operators. The overall numbers of coronary angiographies increased from 1992 to 2003 from 684,000 to 1,993,000 (from 1,250 to 3,500 per million inhabitants). The respective numbers for percutaneous coronary interventions (PCI-coronary angioplasty) and coronary stenting procedures increased from 184,000 to 733,000 (from 335 to 1,300) and from 3,000 to 610,000 (from 5 to 1,100), respectively. Germany has been the most active country for the past years with 653,000 angiographies (7,800), 222,000 angioplasties (2,500), and 180,000 stenting procedures (2,200) in 2003. The indication has shifted towards acute coronary syndromes, as demonstrated by raising rates of interventions for acute myocardial infarction over the last decade. The procedures are more readily performed and safer, as shown by increasing rate of “ad hoc” PCI and decreasing need for emergency coronary artery bypass surgery (CABG). In 2003, use of drug-eluting stents had further increased. However, an enormous variability is reported with the highest rate in Portugal (55%). Conclusion: Interventional cardiology in Europe is still expanding, mainly but not exclusively due to rapid growth in the eastern European countries. A number of new coronary revascularization procedures introduced over the years have all but disappeared. Only stenting has experienced an exponential growth. The same can be forecast for drug-eluting stenting

Heavy metals in soils in middle Spiš

Soil samples were collected in long term contaminated and hygienic loaded area in middle Spiš. In this work we were determining contents of cooper, lead, zinc, chrome and nickel and compared with highest available concentrations. The content of cuprum, lead and zinc exceeded reference and for cooper and lead also indicated values. Cumulation of monitoring risk elements in soil raised order Cu>Zn>Pb>Cr>Ni

The Scavenging of DPPH, Galvinoxyl and ABTS Radicals by Imine Analogs of Resveratrol

Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin produced by plants. Resveratrol is known for its anti-cancer, antiviral and antioxidant properties. We prepared imine analogs of resveratrol ((hydroxyphenyliminomethyl)phenols) and tested their antioxidant activity. All prepared resveratrol analogs were able to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR) and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The antioxidant activity efficiency correlated with the number and position of hydroxyl groups. The most effective antioxidants were resveratrol analogs containing three hydroxyl groups in the benzylidene part of their molecules. These results provide new insights into the relationship between the chemical structure and biological activity of resveratrol analogs

Synthesis and Free Radical Scavenging Activity of New Hydroxybenzylidene Hydrazines

Hydroxybenzylidene hydrazines exhibit a wide spectrum of biological activities. Here, we report synthesis and free radical scavenging activity of nine new N-(hydroxybenzylidene)-N′-[2,6-dinitro-4-(trifluoromethyl)]phenylhydrazines. The chemical structures of these compounds were confirmed by 1H-NMR, 13C-NMR, 19F-NMR, IR spectroscopy, LC-MS, and elemental analysis. The prepared compounds were tested for their activity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical (GOR), and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) radicals. The free radical scavenging activity expressed as SC50 values of these compounds varied in a wide range, from a strong to no radical scavenging effect. The most effective radical scavengers were hydroxybenzylidene hydrazines containing three hydroxyl groups in the benzylidene part of their molecules. The prepared compounds were also tested for their activity to inhibit photosynthetic electron transport in spinach chloroplasts. IC50 values of these compounds varied in wide range, from an intermediate to no inhibitory effect

Phase 1A safety assessment of intravenous amitriptyline

The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. PERSPECTIVE: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pai