Assessment of the sensitizing potential of textile disperse dyes and some of their metabolites by the loose-fit coculture-based sensitization assay (LCSA)

Certain textile disperse dyes are known to cause allergic reactions of the human skin. Here, we examined 8 disperse dyes and 7 products of azo-cleavage of these dyes in an in vitro assay. We used the loose-fit coculture-based sensitization assay (LCSA) of primary human keratinocytes and of allogenic dendritic cell-related cells for combined testing of the sensitizing and irritative properties of these substances. The obtained data were compared to data generated in a modified version of the local lymph node assay by our working group. Disperse Blue 1 (DB1), p-nitroaniline (pNA) and p-aminoacetanilide (AAA) showed no sensitizing potential under our experimental conditions. Disperse Blue 124 (DB124), Disperse Yellow 3 (DY3), Disperse Orange 37/76 (DO37), Disperse Blue 106 (DB106), Disperse Red 1 (DR1), 2-amino-p-cresol (ApC), Disperse Orange 3 (DO3) and 2,6-dichloro-4-nitroaniline (DCh) were categorized as extreme sensitizers. Para-phenylenediamine (pPD) was categorized as strong sensitizer, and 2-amino-5-nitrothiazole (ANT) and 2-(N-ethylanilino)-ethanol (EAE) as weak sensitizers. All dyes, except for DB1, and ApC turned out to be strong irritants. DB1, ANT and DCh showed only weak irritative potential. PPD, pNA, EAE and AAA did not show any irritative effect at the concentration range tested. These results correlate with data derived from the modified version of LLNA and human data. Therefore, the LCSA represents a suitable test system to simultaneously analyse two crucial properties of substances relevant for allergy induction.     

The impact of racial and ethnic disparities in inhaled corticosteroid adherence on healthcare expenditures in adults with asthma

Purpose: The purpose of this study is to determine racial and ethnic disparities with the adherence to inhaled corticosteroids (ICSs) in adults with persistent asthma, and their association with healthcare expenditures.

Methods: A retrospective, cross-sectional study using the Medical Expenditure Panel Survey (MEPS) 2013–2014 data included patients ≥18 years with persistent asthma. Median medication possession ratio (MPR) was used to dichotomize adherence levels. Multivariate regression analysis was conducted to ascertain the association between adherence and race/ethnicity. Total expenditures and association with adherence were analyzed using a generalized linear model with a log link function and gamma distribution. Unadjusted expenditures were compared after bootstrapping.

Results: The average MPR of ICSs for the sample of 277 patients was 0.34. The average MPR level was 0.33 among whites, 0.37 among African-Americans and 0.35 among other minorities. The average MPR was 0.30 among Hispanics, and 0.35 among non-Hispanics. African-Americans were less likely to be adherent than whites (OR 0.95). Hispanics were less likely to be adherent (OR 0.4; CI 0.206–0.777). Higher adherence was associated with significantly higher total health expenditure than lower adherence ($19,223 vs. $12,840 respectively, p?<?.0001). African-Americans had slightly higher total expenditure compared to whites; however, other minorities had significantly lower health expenditures compared to whites (p?=?.01). Non-Hispanics spent significantly less on healthcare compared to Hispanics (p?=?.04).

Conclusions: Valuable insight into the economic cost of the disparities as they relate to persistent asthma provides further evidence of possible ethnic inequities that warrant addressing.     

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6?h) followed by controlled release for 14–16?h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.     

Quantitative structure–activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.     

Aldol derivatives of Thioxoimidazolidinones as potential anti-prostate cancer agents

The paper discusses the synthesis and stereochemical aspects of the anti aldol products, 3-(substituted phenyl)-5-[(substituted phenyl) hydroxy methyl]-5-methyl-4-oxo-2-thioxoimidazolidines. The stereochemistry observed in the aldol reactions with benzaldehydes was explained by transition state model of the endocyclic (E)-enolate formed from the rigid 4-oxo-2-thioxoimidazolidine skeleton. Proton NMR and ROESY spectral analyses were carried out to identify the syn and anti conformations of the aldol diastereomers. Configurations of the enantiomers of the representative anti aldol product 3-(4-chlorophenyl)-5-[(4-chlorophenyl) hydroxy methyl]-5-methyl-4-oxo-2-thioxoimidazolidine was determined by single crystal XRD studies. The compounds were screened in vitro against prostate cancer cell lines, PC-3 and LNCaP and the most potent derivatives were identified.     

An unusual cause of macular infarction: protein-losing enteropathy

Protein-losing enteropathy is a multisystem disorder characterized by abnormally high loss of plasma proteins in the gastrointestinal tract. In addition to loss of plasma proteins there is also loss of anticoagulant globulins leading to a prothrombotic state in the body. Single case observation. The patient developed unilateral macular infarction with non-embolic cerebral infarct due to loss of Antithrombin 3 and Protein S proteins in the gastrointestinal tract. The patient had poor recovery of vision due to severe ischemic retinal injury. The gastroenterology team should be on an alert to rule out prothrombotic states in such patients to prevent such complications.     

Quality-Adjusted Life-Year Losses Averted With Every COVID-19 Infection Prevented in the United States

ObjectiveTo estimate the overall quality-adjusted life-years (QALYs) gained by averting 1 coronavirus disease 2019 (COVID-19) infection over the duration of the pandemic.MethodsA cohort-based probabilistic simulation model, informed by the latest epidemiological estimates on COVID-19 in the United States provided by the Centers for Disease Control and Prevention and literature review. Heterogeneity of parameter values across age group was accounted for. The main outcome studied was QALYs for the infected patient, patient’s family members, and the contagion effect of the infected patient over the duration of the pandemic.ResultsAverting a COVID-19 infection in a representative US resident will generate an additional 0.061 (0.016-0.129) QALYs (for the patient: 0.055, 95% confidence interval [CI] 0.014-0.115; for the patient’s family members: 0.006, 95% CI 0.002-0.015). Accounting for the contagion effect of this infection, and assuming that an effective vaccine will be available in 3 months, the total QALYs gains from averting 1 single infection is 1.51 (95% CI 0.28-4.37) accrued to patients and their family members affected by the index infection and its sequelae. These results were robust to most parameter values and were most influenced by effective reproduction number, probability of death outside the hospital, the time-varying hazard rates of hospitalization, and death in critical care.ConclusionOur findings suggest that the health benefits of averting 1 COVID-19 infection in the United States are substantial. Efforts to curb infections must weigh the costs against these benefits.