Should methods of correction for multiple comparisons be applied in pharmacovigilance?

Purpose. In pharmacovigilance, spontaneous reporting databases are devoted to the early detection of adverse event ‘signals’ of marketed drugs. A common limitation of these systems is the wide number of concurrently investigated associations, implying a high probability of generating positive signals simply by chance. However it is not clear if the application of methods aimed to adjust for the multiple testing problems are needed when at least some of the drug-outcome relationship under study are known. To this aim we applied a robust estimation method for the FDR (rFDR) particularly suitable in the pharmacovigilance context. Methods. We exploited the data available for the SAFEGUARD project to apply the rFDR estimation methods to detect potential false positive signals of adverse reactions attributable to the use of non-insulin blood glucose lowering drugs. Specifically, the number of signals generated from the conventional disproportionality measures and after the application of the rFDR adjustment method was compared. Results. Among the 311 evaluable pairs (i.e., drug-event pairs with at least one adverse event report), 106 (34%) signals were considered as significant from the conventional analysis. Among them 1 resulted in false positive signals according to rFDR method. Conclusions. The results of this study seem to suggest that when a restricted number of drug-outcome pairs is considered and warnings about some of them are known, multiple comparisons methods for recognizing false positive signals are not so useful as suggested by theoretical considerations

Long-Term Changes in the Zooplankton Community of Lake Maggiore in Response to Multiple Stressors: A Functional Principal Components Analysis

We describe the long-term (1981−2008) dynamics of several physico-chemical and biological variables and how their changes may have influenced zooplankton structure in Lake Maggiore (Italy). Data was available for the 1981−1992 and 1995−2008 periods. Standardized time-series for temperature and total phosphorus (TP), chlorophyll-a, phytoplankton density (cel m−3), and cell size (µm3), as well as zooplankton structure (Copepoda, Cladocera, and Rotifera density, ind m−3) were smoothed using penalized B-splines and analyzed using Functional Principal Components (FPCs) to assess their dominant modes of variation. The first four FPCs explained 55% of 1981−1992 and 65% of 1995−2008 overall variation. Results showed that temperature fluctuated during the study period, particularly during 1988−1992 with a general tendency to increase. TP showed a declining trend with some reversions in the pattern observed in the years 1992, 1999, and 2000. Phytoplankton estimators and chlorophyll-a concentration showed a variable trend along the study period. Zooplankton groups also had a variable trend along the study period with a general increase in density of large carnivorous (mainly Bythotrephes longimanus) and a decrease of large herbivorous (mainly Daphnia), and a similar increase in the ratio of raptorial to microphagous rotifers. Our results suggest that the lake experienced a strong trophic change associated with oligotrophication, followed by pronounced climate-induced changes during the latter period. TP concentration was strongly associated with changes in abundance of some zooplankton taxa

Reply to "MDPV-induced aggression in humans not established"

Reply to the the comments made by KY O’Malley and C Medina-Kirchner on the manuscript "Acute and repeated administration of MDPV increases aggressive behavior in mice: forensic implications"

Persistence with inhaled corticosteroids reduces the risk of exacerbation among adults with asthma: A real-world investigation

Real-world evidence suggests that persistence with inhaled corticosteroids (ICS), the mainstay of asthma drug therapy, is generally poor. The effect of persistence with ICS on the risk of asthma exacerbation was addressed in a population-based study

Metabolic profile and pharmaco-toxicological effects of MPA in mouse model

Methiopropamine (MPA) is a thiophene ring-based structural analog of methamphetamine that is categorized as a novel psychoactive substance. MPA acts primary as a norepinephrine-dopamine reuptake inhibitor and, secondary, as a serotonin reuptake inhibitor. In human, MPA induces stimulation, alertness and increase of focus and energy. However, important side-effects were reported after MPA administration such as tachycardia, anxiety, panic attacks, perspiration, headache and difficulty in breathing. To date, few data are available on the pharmaco-toxicological effects of MPA and on its metabolism in vivo. To this purpose we investigated the acute in vivo effects induced by MPA on visual, acoustic and tactile sensorimotor responses, body temperature, pain threshold, motor activity, cardiovascular and cardiorespiratory changes in CD-1 male mice. In vitro (from human liver microsomes preparation) and in vivo (from CD-1 male mice urine) metabolism studies were also conducted in order to characterize the phase I metabolic profile of MPA, with the aim to select both the best marker(s) of intake and the responsible of the potential behavioural effects. Systemic administration of MPA (0.01-30 mg/kg) impaired visual placing response, facilitated acoustic and tactile response, induced hypothermia, increased mechanical and thermal analgesia stimulated locomotor activity and induced motor stereotypies in mice. MPA strongly affected cardiovascular and respiratory parameters. It induced tachycardia, increased diastolic and systolic blood pressure, caused vasoconstriction. Moreover, MPA increased breath rate but it reduced SpO2 saturation. The acute administration of MPA at 10 and 30 mg/kg caused the death (~30% and ~40%, respectively) of mice. Metabolism studies show that MPA is exensively oxidated to form mainly nor-MPA, hydroxy-MPA, oxo-MPA. The best markers of intake and the compounds detected in huge amount during the behavioural tests are the MPA itself and its hydroxylated and demethylated metabolites. The experimental evidence obtained in this study demonstrates for the first time that MPA impairs sensorimotor responses, has psychostimulant effect, causes cardiovascular and respiratory alterations, thus suggesting its possible hazard for human health. This research has been funded by the Drug Policies Department, Presidency of the Council of Ministers, Italy (project: “Effects of NPS: development of a multicentric research for the information enhancement of the Early Warning System” to MM) and FIRB 2012 to FDG

A validation study of a new classification algorithm to identify rheumatoid arthritis using administrative health databases: Case-control and cohort diagnostic accuracy studies. Results from the RECord linkage on Rheumatic Diseases study of the Italian Society for Rheumatology

none13noCarrara, Greta; Scirè, Carlo A.; Zambon, Antonella; Cimmino, Marco A.; Cerra, Carlo; Caprioli, Marta; Cagnotto, Giovanni; Nicotra, Federica; Arfè, Andrea; Migliazza, Simona; Corrao, Giovanni; Minisola, Giovanni; Montecucco, CarlomaurizioCarrara, Greta; Scire', CARLO ALBERTO; Zambon, Antonella; Cimmino, Marco A.; Cerra, Carlo; Caprioli, Marta; Cagnotto, Giovanni; Nicotra, Federica; Arfè, Andrea; Migliazza, Simona; Corrao, Giovanni; Minisola, Giovanni; Montecucco, Carlomaurizi

Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs : A multi-country european database study within the SOS Project

Background and purpose A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. Methods Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. Results 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02–1.15) and use of traditional NSAIDs (1.16, 1.12–1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19–1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. Conclusions Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13–46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage