What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 2: systemic therapies.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Impact of AhRR (565C > G) polymorphism on dioxin dependent CYP1A2 induction.

The current study uses the metabolic probe, antipyrine, and AhRR transcript expression (qRT-PCR) to examine the impact of the AhRR (565C > G or Pro185Ala, rs2292596) genetic polymorphism upon CYP1A2 inducibility in an established cohort of male firefighters with exposure to dioxin-like chemicals. The lipid adjusted concentrations of 29 dioxin and dioxin-like congeners were measured in serum. Possession of the G allele (CG and GG genotypes) was correlated with high expression AhRR transcript and lower CYP1A2 induction than found in individuals homozygous for CC. The induction of CYP1A2 was dioxin-dependent among carriers of the G allele. Multivariate models indicated that CYP1A2 activity, detected as urinary 3-hydroxymethylantipyrine, was significantly correlated with cotinine concentration and for those currently working as firefighters, dioxin body burden (ß = 0.54, p = 0.041). The efficacy of the AhRR in regulating the AhR signaling pathway is influenced by the AhRR (565C > G) polymorphism. Our study of firefighters using the induction of CYP1A2 as an indicator suggest that G allele proteins have variable AhR repressor activity which is manifested in a dioxin-dependent manner. These results provide evidence of metabolic differences that may affect susceptibility to dioxin-mediated health effects.

Evaluation of the impact of CYP1A2 induction by charbroiled meal on metabolic phenotype.

BACKGROUND & AIMS: The process of grilling food items often generates polycyclic aromatic hydrocarbons which are established inducers of CYP1A2, a human drug metabolising enzyme, known to activate some procarcinogens. The impact of such induction on CYP1A2 metabolic phenotype has been the subject of some discordant findings. This study, while considering some limitations in previous study designs, evaluated the effect of CYP1A2 induction by the consumption of charbroiled meal on its metabolic phenotype. METHODS: Caffeine was administered to 17 healthy subjects before, and after, four consecutive days of charbroiled beef ingestion. Blood and spot urine samples were subsequently collected at the 4th and 6th hour post caffeine-administration, respectively, for the assessment of CYP1A2 activity. An additional caffeine administration and sample collection was repeated 48 h after the cessation of charbroiled-beef intake. CYP1A2 activity, derived as the log-transformed molar ratios of caffeine and its metabolites, was statistically analysed for changes in metabolic phenotype. RESULTS: Urinary and plasma metrics of CYP1A2 activity had mean reference values of 1.53 and 0.38, respectively, in the study subjects. CYP1A2 metabolic phenotype before and after the ingestion of charbroiled meal was not significantly different. However, urinary and plasma metrics of CYP1A2 activity decreased by about 19% (1.53 vs 1.24) and 65% (0.38 vs 0.14), respectively, 48 h after the cessation of charbroiled meal ingestion. CONCLUSIONS: The induction of CYP1A2 by the consumption of charbroiled meals may not portend increased rate of CYP1A2-activation of procarcinogens in humans. However, a potentially significant CYP1A2 inhibition which might result in increased-exposure for drugs predominantly metabolised by this enzyme is likely.

Development of Left Atrial Thrombus After Coadministration of Dabigatran Etexilate and Phenytoin.

Dabigatran etexilate is a substrate of the P-glycoprotein (adenosine triphosphate-binding cassette subfamily B member 1) transport system and is subject to interactions with medications that induce or inhibit this system. The clinical relevance of the interaction between dabigatran and phenytoin has not been well described. We report a case of left atrial thrombus in a patient receiving concomitant dabigatran etexilate and phenytoin, which is a P-glycoprotein inducer. This case illustrates the potential clinical significance of the interactions of medications that affect P-glycoprotein and dabigatran.

Impact of dioxins on antipyrine metabolism in firefighters.

Antipyrine (AP) metabolism was used to assess factors associated with the activity of hepatic oxidative enzymes in firefighters. Emphasis was placed on 3-hydroxymethylantipyrine (3HMAP), the metabolite with the greatest dependence on dioxin-inducible cytochrome P4501A2 (CYP1A2) activity. AP urinary metabolites were measured by HPLC in 38 male subjects from Eastern Siberia. Subjects were divided into three groups having similar ages and BMIs: current firefighters (n=11); former firefighters (n=17) and non-firefighters (n=10). Multiple regression models were constructed using the three major AP metabolites as a dependent variable to assess the influence of age, smoking as urinary cotinine concentration, dioxin exposure (as either WHO-TEQ or body burden), group, and CYP1A2*F (-163C>A) genotypes. Models for the proportion of dose excreted as the metabolite 3HMAP produced the best fit (adjusted R(2)=0.46, p<0.05). When the models were restricted to current firefighters, only those based on 3HMAP were statistically significant (adjusted R(2) of 0.80 (p<0.002)) due to contributions from urinary cotinine (ß=0.56, p<0.01) and dioxin expressed as body burden (ß=0.55, p=0.014). These results indicate that the antipyrine test can be used as metabolic probe of biological response to recent dioxin exposure provided the impact of smoking is carefully controlled.