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

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Cancer cells in hypoxic areas of solid tumors are to a large extent protected against the action of radiation as well as many chemotherapeutic drugs. There are, however, two different aspects of the problem caused by tumor hypoxia when cancer therapy is concerned: One is due to the chemical reactions that molecular oxygen enters intoin therapeutically targeted cells. This results in a direct chemical protection against therapy by the hypoxic microenvironment which has little to do with cellular biological regulatory processes. This part of the protective effect of hypoxia has been known for more than half a century and has been studied extensively. However, in recent years more focus has been put into the other aspect of hypoxia, namely the effect of this microenvironmental condition on selecting cells with certain genetical pre-requisites that are negative with respect to patient prognosis. There are adaptive mechanisms, where hypoxia induces regulatory cascades in cells resulting in a changed metabolism or changes in extra cellular signalling. These processes may lead to changes in cellular intrinsic sensitivity to treatment irrespective of oxygenation and furthermore, may also have consequences for tissue organization. Thus, the adaptive mechanisms induced by hypoxia itself may have a selective effect on cells with a fine-tuned protection against damage and stress of many kinds. It therefore could be that the adaptive mechanisms may be taken advantage of for new tumor labelling/imaging and treatment strategies. One of the Achilles’ heels of hypoxia research has always been exact measurements of tissue oxygenation as well as control of oxygenation in biological tumor models. Thus, development of technology that can ease this control is vital in order to study mechanisms and perform drug development under relevant conditions. An integrated EU Framework project 2004-2009, termed Euroxy, demonstrates several pathways involved in transcription and translation control of the hypoxic cell phenotype and evidence of cross talk with responses to pH and redox changes. The carbon anhydrase isoenzyme CA IX was selected for further studies due to its expression on the surface of many types of hypoxic tumors. The effort has lead to marketable culture flaks with sensors and incubation equipment and the synthesis of new drug candidates against new molecular targets. New labelling/imaging methods for cancer diagnosing and imaging of hypoxic cancer tissue now are being tested in xeno-graft models and also are in early clinical testing while new potential anticancer drugs are undergoing tests using xenografted tumor cancers. The present paper describes the above results in individual consortium partner presentations

Blended CBT versus face-to-face CBT: a randomised non-inferiority trial.

BACKGROUND: Internet based cognitive behavioural therapy (iCBT) has been demonstrated to be cost- and clinically effective. There is a need, however, for increased therapist contact for some patient groups. Combining iCBT with traditional face-to-face (ftf) consultations in a blended format (B-CBT) may produce a new treatment format with multiple benefits from both traditional CBT and iCBT such as individual adaptation, lower costs than traditional therapy, wide geographical and temporal availability, and possibly lower threshold to implementation. The primary aim of the present study is to compare directly the clinical effectiveness of B-CBT with face-to-face CBT for adult major depressive disorder. METHODS/DESIGN: The study is designed as a two arm randomised controlled non-inferiority trial comparing blended CBT for adult depression with treatment as usual (TAU). In the blended condition six sessions of ftf CBT is alternated with six to eight online modules (NoDep). TAU is defined as 12 sessions of ftf CBT. The primary outcome is symptomatic change of depressive symptoms on the patient-health questionnaire (PHQ-9). Additionally, the study will include an economic evaluation. All participants must be 18 years of age or older and meet the diagnostic criteria for major depressive disorder according to the Diagnostic and Statistical Manual of Mental disorders 4th edition. Participants are randomised on an individual level by a researcher not involved in the project. The primary outcome is analysed by regressing the three-month follow-up PHQ-9 data on the baseline PHQ-9 score and a treatment group indicator using ancova. A sample size of 130 in two balanced groups will yield a power of at least 80% to detect standardised mean differences above 0.5 on a normally distributed variable. DISCUSSION: This study design will compare B-CBT and ftf CBT in a concise and direct manner with only a minimal of the variance explained by differences in therapeutic content. On the other hand, while situated in routine care, ecological validity is somewhat compromised by the controlled manner in which the study is conducted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02796573 . Registered June 1st 2016. Currently recruiting participants