PP016—Exposure to antipsychotics with pro-arrhythmic risk: Combining adverse drug reactions with drug utilization data

e22 Volume 35 Number 8S Department of Clinical Pharmacology, and Department of Dentistry, Oral and Maxillofacial Surgery; Department of Clinical Pharmacology; and Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Shimotsukeshi, Japan Introduction: Docetaxel, cisplatin plus 5-FU (DCF) regimen is a useful chemotherapy against malignant diseases such as advanced head and neck cancer. However, DCF regimen is sometimes withdrawn by severe myelosuppression and nonhematologic toxic effects, including mucositis. Previous animal and clinical studies showed that the degrees of docetaxel-, cisplatin-, and 5-FU–induced toxicities depend on their dosing time. We have reported that the frequency of docetaxel-induced intestinal mucositis was greater after dosing at an active phase than at an inactive phase in mice. The aim of the present study was to determine the influence of dosing schedule of DCF regimen on chemotherapy-induced toxicities in clinical practice. Patients (or Materials) and Methods: Patients with oral squamous cell carcinoma treated with DCF regimen were randomly allocated to the following 2 groups: chemotherapy started from morning (10:30) in the first group and evening (18:30) in the second group. Hematologic and nonhematologic adverse effects were assessed for 14 days after the start of chemotherapy. Results: The most frequently observed mild to severe adverse effects were neutropenia, diarrhea, stomatitis, and nausea. The frequency of grade 3 to 4 neutropenia was 62.5% (5 of 8) in the morning group and 28.6% (2 of 7) in the evening group. Grade 3 to 4 event of stomatitis and grade 3 event of nausea were more detected in the morning group. Conclusion: These findings suggest that chronotherapy of DCF regimen might diminish severe adverse effects in patients with oral squamous cell carcinoma. Disclosure of Interest: None declared

Detection of Newly Described Astrovirus MLB1 in Stool Samples from Children

The prevalence of the recently identified astrovirus MLB1 in a cohort of children with diarrhea in St. Louis, Missouri, USA, was defined by reverse transcription–PCR. Of 254 stool specimens collected in 2008, 4 were positive for astrovirus MLB1. These results show that astrovirus MLB1 is circulating in North America

The AMANDA Neutrino Telescope: Principle of Operation and First Results

AMANDA is a high-energy neutrino telescope presently under construction at the geographical South Pole. In the Antarctic summer 1995/96, an array of 80 optical modules (OMs) arranged on 4 strings (AMANDA-B4) was deployed at depths between 1.5 and 2 km. In this paper we describe the design and performance of the AMANDA-B4 prototype, based on data collected between February and November 1996. Monte Carlo simulations of the detector response to down-going atmospheric muon tracks show that the global behavior of the detector is understood. We describe the data analysis method and present first results on atmospheric muon reconstruction and separation of neutrino candidates. The AMANDA array was upgraded with 216 OMs on 6 new strings in 1996/97 (AMANDA-B10), and 122 additional OMs on 3 strings in 1997/98.Comment: 36 pages, 23 figures, submitted to Astroparticle Physic

The Contribution of National Spontaneous Reporting Systems to Detect Signals of Torsadogenicity: Issues Emerging from the ARITMO Project

Introduction: Spontaneous reporting systems (SRSs) are pivotal for signal detection, especially for rare events with a high drug-attributable component, such as torsade de pointes (TdP). Use of different national SRSs is rarely attempted because of inherent difficulties, but should be considered on the assumption that rare events are diluted in international databases. Objective: The aim was to describe TdP-related events associated with antipsychotics, H1-antihistamines and anti-infectives in three national SRSs (in Italy, Germany and France) and highlight potential signals of torsadogenicity through a combined literature evaluation. Methods: A common search strategy was applied to extract TdP-related events: (1) TdP, (2) QT interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. Signals of disproportionate reporting (SDRs) were calculated for TdP + QT interval abnormalities and defined by a lower limit of the 95 % confidence interval of the reporting odds ratio (ROR) >1. Among SDRs with at least three cases without concomitant pro-arrhythmic drugs, we defined potential new signal of torsadogenicity as drugs with no published evidence from (a) the crediblemeds® website (http://www.crediblemeds.com, as of November 1st, 2014); (b) studies on the FDA Adverse Event Reporting System (FAERS); and (c) safety trials or pharmaco-epidemiological studies (as of December 16th, 2014). Results: Overall, 3505 cases were retrieved (1372, 1468, and 801 for France, Germany and Italy, respectively). Antipsychotics were mainly recorded in Germany (792 cases), whereas antibiotics peaked at 515 and 491 (France and Italy, respectively). Forty-one drugs met criteria for SDRs in at least one single source, of which 31 were detected only from one single SRS: 18, ten and three (French, German and Italian SRS, respectively). By contrast, only five SDRs were detected in all national data sources (amisulpride, aripiprazole, haloperidol, olanzapine, risperidone). Overall, five potential new signals of torsadogenicity were identified: flupentixol, ganciclovir, levocetirizine, oxatomide and tiapride. Conclusions: We found differences across and within national SRSs in the reporting of drug-induced TdP, which finally resulted in five potential new signals of torsadogenicity. These findings warrant targeted pharmacovigilance studies to formally assess the existence of actual drug–event associations

Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database

Background: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk

The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections

Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self-administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein-bound Cys concentrations while LS level was unchanged. Cocaine self-administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration

Results from the Antarctic Muon and Neutrino Detector Array (AMANDA)

We show new results from both the older and newer incarnations of AMANDA (AMANDA-B10 and AMANDA-II, respectively). These results demonstrate that AMANDA is a functioning, multipurpose detector with significant physics and astrophysics reach. They include a new higher-statistics measurement of the atmospheric muon neutrino flux and preliminary results from searches for a variety of sources of ultrahigh energy neutrinos: generic point sources, gamma-ray bursters and diffuse sources producing muons in the detector, and diffuse sources producing electromagnetic or hadronic showers in or near the detector.Comment: Invited talk at the XXth International Conference on Neutrino Physics and Astrophysics (Neutrino 2002), Munich, Germany, May 25-30, 200

Limits to the muon flux from WIMP annihilation in the center of the Earth with the AMANDA detector

A search for nearly vertical up-going muon-neutrinos from neutralino annihilations in the center of the Earth has been performed with the AMANDA-B10 neutrino detector. The data sample collected in 130.1 days of live-time in 1997, ~10^9 events, has been analyzed for this search. No excess over the expected atmospheric neutrino background is oberved. An upper limit at 90% confidence level on the annihilation rate of neutralinos in the center of the Earth is obtained as a function of the neutralino mass in the range 100 GeV-5000 GeV, as well as the corresponding muon flux limit.Comment: 14 pages, 11 figures. Version accepted for publication in Physical Review