Access to the CNS: Biomarker Strategies for Dopaminergic Treatments

Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson's disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development.Pharmacolog

Replicability and Generalizability of Posttraumatic Stress Disorder (PTSD) Networks: A Cross-Cultural Multisite Study of PTSD Symptoms in Four Trauma Patient Samples

The growing literature conceptualizing mental disorders like posttraumatic stress disorder (PTSD) as networks of interacting symptoms faces three key challenges. Prior studies predominantly used (a) small samples with low power for precise estimation, (b) nonclinical samples, and (c) single samples. This renders network structures in clinical data, and the extent to which networks replicate across data sets, unknown. To overcome these limitations, the present cross-cultural multisite study estimated regularized partial correlation networks of 16 PTSD symptoms across four data sets of traumatized patients receiving treatment for PTSD (total N = 2,782). Despite differences in culture, trauma type, and severity of the samples, considerable similarities emerged, with moderate to high correlations between symptom profiles (0.43-0.82), network structures (0.62-0.74), and centrality estimates (0.63-0.75). We discuss the importance of future replicability efforts to improve clinical psychological science and provide code, model output, and correlation matrices to make the results of this article fully reproducible

ANTIOXIDANT AND ANTIMICROBIAL ACTIVITIES OF THE ESSENTIAL OIL AND SOLVENT EXTRACTS OF MENTHA PULEGIUM L.

We report the total phenolic (TPC; expressed as gallic acid equivalents, GAE, per milligram of dry extract weight) and the total flavonoid contents (TFC; expressed as quercetin equivalents, QE, per milligram of dry extract weight) and antimicrobial and antioxidant activities of the essential oil and hexane, diethyl ether, ethyl acetate and methanol extracts of Mentha pulegium L. (Lamiaceae) collected in Serbia. The total phenolic content was in the range of 129.43-388.29 μg GAE/mg, while TFC ranged from 57.81 to 160.94 QE/mg; the highest TPC and TFC were found in the methanol extract. The antimicrobial activity (against five bacteria and two fungi species) of the essential oil and solvent extracts was assessed using disc-diffusion method. However, the studied samples demonstrated a poor antimicrobial potential. The antioxidant activity was screened using five different tests: 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid radical cation decolorization assay (ABTS), total reducing power (TRP), ferric reducing antioxidant power (FRAP) and cupric reducing antioxidant capacity assay (CUPRAC); the methanol extract showed the strongest antioxidant potential. The results of the different antioxidant assays were correlated mutually and with the total flavonoid and total phenolic contents (regression analysis and agglomerative hierarchical clustering). ANTIOKSIDANTNA I ANTIMIKROBNA AKTIVNOST ETARSKOG ULJA I EKSTRAKATA BILJNE VRSTE MENTHA PULEGIUM L.U ovom radu je određen sadržaj ukupnih fenola (TPC; izražen u ekvivalentima galne kiseline, GAE, po miligramu suvog biljnog ekstrakta) i ukupnih flavonoida (TPC; izražen u ekvivalentima kvarcetina, QE, po miligramu suvog biljnog ekstrakta), kao i antimikrobna i antioksidantna aktivnost etarskog ulja i heksanskog, dietil-etarskog, etil-acetatnog i metanolnog ekstrakta biljne vrste Mentha pulegium L. (Lamiaceae; populacija iz Srbije). Sadržaj ukupnih fenola analiziranih uzoraka se kretao u opsegu od 129,43 do 388,29 μg GAE/mg, dok je TFC bio u interval od 57,81 do 160,94 QE/mg; najviše vrednosti za TPC i TFC nađene su za metanolni ekstrakt. Antimikrobna aktivnost (prema pet bakterijskih i dva soja gljivica) etarskog ulja i ekstrakata je određena disk-difuzionom metodom. Proučavani uzorci su imali slabu antimikrobnu aktivnost. Antioksidantna aktivnost je ispitivana pomoću DPPH (2,2-difenil-1-pikrilhidrazil radikal), ABTS (2,2'-azino-bis(3-etilbenzotijazolin-6-sulfonska kiselina radikal katjon), TRP (ukupna redukciona sposobnost), FRAP (sposobnost redukcije feri-jona) i CUPRAC (sposobnost redukcije Cu(II)-jona) metodama; najviši antioksidantni potencijal je imao metanolni ekstrakt. Rezultati različitih metoda za određivanje antioksidantnog potencijala su korelisani međusobno, kao i sa sadržajem ukupnih fenola i flavonoida (regresiona analiza i aglomerativna hijerarhijska klaster analiza). HIGHLIGHTSThe essential oil and hexane, diethyl ether, ethyl acetate and methanol extracts of Mentha pulegium L. collected in Serbia were studied.Their total phenolic content was in the range of 129.43-388.29 μg GAE/mg, while total flavonoid content ranged from 57.81 to 160.94 QE/mg.Solvent extracts (SE) and essential oil of the studied M. pulegium population were poor antimicrobials.Antioxidant activities of SE were studied using five different methods.Differences between the previous and the present results suggest M. pulegium metabolic profile might be influenced by both genetic and environmental factors

A Pediatric Covariate Function for CYP3A-Mediated Midazolam Clearance Can Scale Clearance of Selected CYP3A Substrates in Children

Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1– 17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information

PTSD-8: A Short PTSD Inventory

Traumatic events pose great challenges on mental health services in scarcity of specialist trauma clinicians and services. Simple short screening instruments for detecting adverse psychological responses are needed. Several brief screening instruments have been developed. However, some are limited, especially in relation to reflecting the posttraumatic stress disorder (PTSD) diagnosis. Recently, several studies have challenged pre-existing ideas about PTSD’s latent structure. Factor analytic research currently supports two four factor models. One particular model contains a dysphoria factor which has been associated with depression and anxiety. The symptoms in this factor have been hailed as less specific to PTSD. The scope of this article is therefore to present a short screening instrument, based on this research; Posttraumatic Stress Disorder (PTSD) – 8 items. The PTSD-8 is shown to have good psychometric properties in three independent samples of whiplash patients (n=1710), rape victims (n=305), and disaster victims (n=516). Good test-rest reliability is also shown in a pilot study of young adults from families with alcohol problems (n=56)

Zebrafish Kidney Phagocytes Utilize Macropinocytosis and Ca2+-Dependent Endocytic Mechanisms

Background: The innate immune response constitutes the first line of defense against invading pathogens and consists of a variety of immune defense mechanisms including active endocytosis by macrophages and granulocytes. Endocytosis can be used as a reliable measure of selective and non-selective mechanisms of antigen uptake in the early phase of an immune response. Numerous assays have been developed to measure this response in a variety of mammalian and fish species. The small size of the zebrafish has prevented the large-scale collection of monocytes/macrophages and granulocytes for these endocytic assays. Methodology/Principal Findings: Pooled zebrafish kidney hematopoietic tissues were used as a source of phagocytic cells for flow-cytometry based endocytic assays. FITC-Dextran, Lucifer Yellow and FITC-Edwardsiella ictaluri were used to evaluate selective and non-selective mechanisms of uptake in zebrafish phagocytes. Conclusions/Significance: Zebrafish kidney phagocytes characterized as monocytes/macrophages, neutrophils and lymphocytes utilize macropinocytosis and Ca 2+-dependant endocytosis mechanisms of antigen uptake. These cells do not appear to utilize a mannose receptor. Heat-killed Edwardsiella ictaluri induces cytoskeletal interactions for internalization in zebrafish kidney monocytes/macrophages and granulocytes. The proposed method is easy to implement and should prove especially useful in immunological, toxicological and epidemiological research

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%