Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events (Review)

Background Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe when used alone or in conjunction with inhaled corticosteroids. Objectives The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone. Search strategy Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was October 2008. Selection criteria Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomised patients to treatment with regular formoterol and inhaled corticosteroids, and were of at least 12 weeks duration. Data collection and analysis Two authors independently selected trials for inclusion in the review. Outcome data were independently extracted by two authors. Unpublished data on mortality and serious adverse events were obtained from the sponsors. Main results The review included 14 studies on adults and adolescents (8,028 participants) and seven studies on children and adolescents (2,788 participants). Data on all cause fatal and non-fatal serious adverse events were found for all studies, and the overall risk of bias was low.Four deaths occurred on regular formoterol with inhaled corticosteroids, and none on regular inhaled corticosteroids alone. All the deaths were in adults, and one was reported to be asthma-related. The difference was not statistically significant. Non-fatal serious adverse events of any cause were very similar in adults [Peto Odds Ratio 0.99 (95% CI 0.74 to 1.33)], and an increase in events in children on regular formoterol was not statistically significant [Peto Odds Ratio 1.62 (95% CI 0.80 to 3.28)]. Asthma related serious adverse events on formoterol were lower in adults [Peto Odds Ratio 0.53 (95% CI 0.28 to 1.00)] and although they were higher in children [Peto Odds Ratio 1.49 ( 95% CI 0.48 to 4.61)], this was not statistically significant. Authors' conclusions It is not possible, from the data in this review, to reassure people with asthma that inhaled corticosteroids with regular formoterol carries no risk of increasing mortality in comparison to inhaled corticosteroids alone as all four deaths occurred among 6,594 people using inhaled corticosteroids with formoterol. On the other hand, we have found no conclusive evidence of harm and there was only one asthma related death registered during over 3,000 patient year observation on formoterol. In adults, the decrease in asthma-related serious adverse events on regular formoterol with inhaled corticosteroids was not accompanied by a decrease in all cause serious adverse events. In children the number of events was too small, and consequently the results too imprecise, to determine whether the increase in all cause non-fatal serious adverse events found in the previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids. Clinical decisions and information for patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty and concern associated with its potential harmful effects

Peroxynitrite formation and sinusoidal endothelial cell injury during acetaminophen-induced hepatotoxicity in mice

INTRODUCTION:Vascular injury and accumulation of red blood cells in the space of Disse (hemorrhage) is a characteristic feature of acetaminophen hepatotoxicity. However, the mechanism of nonparenchymal cell injury is unclear. Therefore, the objective was to investigate if either Kupffer cells or intracellular events in endothelial cells are responsible for the cell damage.RESULTS:Acetaminophen treatment (300 mg/kg) caused vascular nitrotyrosine staining within 1 h. Vascular injury (hemorrhage) occurred between 2 and 4 h. This paralleled the time course of parenchymal cell injury as shown by the increase in plasma alanine aminotransferase activities. Inactivation of Kupffer cells by gadolinium chloride (10 mg/kg) had no significant effect on vascular nitrotyrosine staining, hemorrhage or parenchymal cell injury. In contrast, treatment with allopurinol (100 mg/kg), which prevented mitochondrial injury in hepatocytes, strongly attenuated vascular nitrotyrosine staining and injury.CONCLUSIONS:Our data do not support the hypothesis that acetaminophen-induced superoxide release leading to vascular peroxynitrite formation and endothelial cell injury is caused by activated Kupffer cells. In contrast, the protective effect of allopurinol treatment suggests that, similar to the mechanism in parenchymal cells, mitochondrial oxidant stress and peroxynitrite formation in sinusoidal endothelial cells may be critical for vascular injury after acetaminophen overdose.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity

Determination of Corresponding Temperature Distribution within CFRP during Laser Cutting

AbstractLaser cutting of carbon fiber reinforced plastics as a thermal process results in a thermal load on the material. Due to the high thermal conductivity of carbon fibers, residual heat is conducted along the fibers, away from the laser interaction zone. Common temperature measurement techniques, such as pyrometry and infrared thermography only allow for observation of the temperature development on the surface of the material. In order to achieve information about the temperature distribution within the material during the cutting process, thermochromes and thermocouples were implemented during the laminating process of CFRP. The cutting tests were performed with a single mode fiber laser emitting a continuous wave and at a wavelength of λ = 1080 nm

Supercell Altermagnets

Altermagnets are compensated magnets with unconvetional $d$, $g$ and $i$-wave spin-channel order in reciprocal space. So far the search for new altermagnetic candidates has been focused on materials in which the magnetic unit cell is identical to the non-magnetic one, i.e. magnetic structures with zero propagation vector. Here, we substantially broaden the family of altermagnetic candidates by predicting supercell altermagnets. Their magnetic unit cell is constructed by enlarging the paramagnetic primitive unit cell, resulting in a non-zero propagation vector for the magnetic structure. This connection of the magnetic configuration to the ordering of sublattices gives an extra degree of freedom to supercell altermagnets, which can allow for the control over the order parameter spatial orientation. We identify realistic candidates MnSe$_2$ with a $d$-wave order, and RbCoBr$_3$, CsCoCr$_3$, and BaMnO$_3$ with $g$-wave order. We demonstrate the reorientation of the order parameter in MnSe$_2$, which has two different magnetic configurations, whose energy difference is only 5 meV, opening the possibility of controlling the orientation of the altermagnetic order parameter by external perturbations.Comment: 10 pages, 4 figure