Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase

Introduction Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine. Objective Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome. Methods Individual case safety reports (ICSRs) for children ≤17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to-expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated. Results There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%). Conclusion Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid

Off-label psychopharmacologic prescribing for children: History supports close clinical monitoring

The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring

Change in dominance determines herbivore effects on plant biodiversity

Herbivores alter plant biodiversity (species richness) in many of the world’s ecosystems, but the magnitude and the direction of herbivore effects on biodiversity vary widely within and among ecosystems. One current theory predicts that herbivores enhance plant biodiversity at high productivity but have the opposite effect at low productivity. Yet, empirical support for the importance of site productivity as a mediator of these herbivore impacts is equivocal. Here, we synthesize data from 252 large-herbivore exclusion studies, spanning a 20-fold range in site productivity, to test an alternative hypothesis—that herbivore-induced changes in the competitive environment determine the response of plant biodiversity to herbivory irrespective of productivity. Under this hypothesis, when herbivores reduce the abundance (biomass, cover) of dominant species (for example, because the dominant plant is palatable), additional resources become available to support new species, thereby increasing biodiversity. By contrast, if herbivores promote high dominance by increasing the abundance of herbivory-resistant, unpalatable species, then resource availability for other species decreases reducing biodiversity. We show that herbivore-induced change in dominance, independent of site productivity or precipitation (a proxy for productivity), is the best predictor of herbivore effects on biodiversity in grassland and savannah sites. Given that most herbaceous ecosystems are dominated by one or a few species, altering the competitive environment via herbivores or by other means may be an effective strategy for conserving biodiversity in grasslands and savannahs globally

Intermaxillary Fixation with Buccolingual Stabilization

Conventionally intermaxillary fixation before fixation of fracture is done from the buccal or labial side. We present a technique of stabilization from both buccal and lingual side which gives three dimensional stability