The Study of the Influence of Formulation and Process Variables on the properties of Simvastatin-Phospholipid Complex

Objectives: The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin-phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin. Method: The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical-chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in-vitro dissolution studies, dissolution efficiency analysis, and ex-vivo permeability studies. Results: The factors studied were found to significantly influence on the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical-chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (\u3e98%), compared to that of pure simvastatin (∼16%). The calculated dissolution efficiency was also found to be significantly higher for the SPC (∼54 %), compared to that of pure simvastatin (∼8%). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (\u3e78%), compared to that of pure simvastatin (∼11%). Implications: The present study shows that simvastatin-phospholipid complex can be a promising strategy for improving the delivery of simvastatin, and similar drugs with low aqueous solubility

Correlation of Solid Dosage Porosity and Tensile Strength with Acoustically Extracted Mechanical Properties

Currently, the compressed tablet and its oral administration is the most popular drug delivery modality in medicine. The accurate porosity and tensile strength characterization of a tablet design is vital for predicting its performance such as disintegration, dissolution, and drug-release efficiency upon administration as well as ensuring its mechanical integrity. In current work, a non-destructive contact ultrasonic approach and an associated testing procedure are presented and employed to quantify and relate the acoustically extracted mechanical properties of pharmaceutical compacts to direct porosity and tensile strength measurements. Based on a comprehensive set of experimental data, it is demonstrated how strongly the acoustic wave propagation is modulated and correlated to the tablet porosity and tensile strength of a compact made using spray-dried lactose and microcrystalline cellulose with varying mixture ratios. The effect of mixing ratio on the porosity and tensile strength on the resulting compacts is quantified and, with the acoustic experimental data, mixing ratio is related to the compact ultrasonic characteristics. The ultrasonic techniques provide a rapid, non-destructive means for evaluating compacts in formulation development and manufacturing. The presented approach and data could find critical applications in continuous tablet manufacturing, its real-time quality monitoring, as well as minimizing batch-to-batch quality variations

The role of phospholipid as a solubility- and permeability-enhancing excipient for the improved delivery of the bioactive phytoconstituents of Bacopa monnieri

In an attempt to improve the solubility and permeability of Standardized Bacopa Extract (SBE), a complexation approach based on phospholipid was employed. A solvent evaporation method was used to prepare the SBE-phospholipid complex (Bacopa Naturosome, BN). The formulation and process variables were optimized using a central-composite design. The formation of BN was confirmed by photomicroscopy, Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction (PXRD). The saturation solubility, the in-vitro dissolution, and the ex-vivo permeability studies were used for the functional evaluation of the prepared complex. BN exhibited a significantly higher aqueous solubility compared to the pure SBE (20-fold), or the physical mixture of SBE and the phospholipid (13-fold). Similarly, the in-vitro dissolution revealed a significantly higher efficiency of the prepared complex (BN) in releasing the SBE (\u3e 97%) in comparison to the pure SCE (~ 42%), or the physical mixture (~ 47%). The ex-vivo permeation studies showed that the prepared BN significantly improved the permeation of SBE (\u3e 90%), compared to the pure SBE (~ 21%), or the physical mixture (~ 24%). Drug-phospholipid complexation may thus be a promising strategy for solubility enhancement of bioactive phytoconstituents

Nanoparticulate matter exposure results in white matter damage and an inflammatory microglial response in an experimental murine model

Exposure to ambient air pollution has been associated with white matter damage and neurocognitive decline. However, the mechanisms of this injury are not well understood and remain largely uncharacterized in experimental models. Prior studies have shown that exposure to particulate matter (PM), a sub-fraction of air pollution, results in neuroinflammation, specifically the upregulation of inflammatory microglia. This study examines white matter and axonal injury, and characterizes microglial reactivity in the corpus callosum of mice exposed to 10 weeks (150 hours) of PM. Nanoscale particulate matter (nPM, aerodynamic diameter ≤200 nm) consisting primarily of traffic-related emissions was collected from an urban area in Los Angeles. Male C57BL/6J mice were exposed to either re-aerosolized nPM or filtered air for 5 hours/day, 3 days/week, for 10 weeks (150 hours; n = 18/group). Microglia were characterized by immunohistochemical double staining of ionized calcium-binding protein-1 (Iba-1) with inducible nitric oxide synthase (iNOS) to identify pro-inflammatory cells, and Iba-1 with arginase-1 (Arg) to identify anti-inflammatory/ homeostatic cells. Myelin injury was assessed by degraded myelin basic protein (dMBP). Oligodendrocyte cell counts were evaluated by oligodendrocyte transcription factor 2 (Olig2). Axonal injury was assessed by axonal neurofilament marker SMI-312. iNOS-expressing microglia were significantly increased in the corpus callosum of mice exposed to nPM when compared to those exposed to filtered air (2.2 fold increase; p\u3c0.05). This was accompanied by an increase in dMBP (1.4 fold increase; p\u3c0.05) immunofluorescent density, a decrease in oligodendrocyte cell counts (1.16 fold decrease; p\u3c0.05), and a decrease in neurofilament SMI-312 (1.13 fold decrease; p\u3c0.05) immunofluorescent density. Exposure to nPM results in increased inflammatory microglia, white matter injury, and axonal degradation in the corpus callosum of adult male mice. iNOS-expressing microglia release cytokines and reactive oxygen/ nitrogen species which may further contribute to the white matter damage observed in this model

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations

A proofreading mutation with an allosteric effect allows a cluster of SARS-CoV-2 viruses to rapidly evolve

The RNA-dependent RNA polymerase of the severe acute respiratory syndrome coronavirus 2 virus is error prone, with errors being corrected by the exonuclease (NSP14) proofreading mechanism. However, the mutagenesis and subsequent evolutionary trajectory of the virus is mediated by the delicate interplay of replicase fidelity and environmental pressures. Here, we have shown that a single, distal mutation (F60S) in NSP14 can have a profound impact upon proofreading with an increased accumulation of mutations and elevated evolutionary rate being observed. Understanding the implications of these changes is crucial, as these underlying mutational processes may have important implications for understanding the population-wide evolution of the virus. This study underscores the urgent need for continued research into the replicative mechanisms of this virus to combat its continued impact on global health, through the re-emergence of immuno-evasive variants

Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model

BACKGROUND: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood–brain barrier weakening, which may augment neurotoxic effects of PM. OBJECTIVES: This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter [Formula: see text]) and CCH secondary to bilateral carotid artery stenosis (BCAS) in a murine model to produce white matter injury. Based on other air pollution interactions, we predicted synergies of nPM with BCAS. METHODS: nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) were randomized to four exposure paradigms: a) FA, b) nPM, c) [Formula: see text] , and d) [Formula: see text]. Behavioral outcomes, white matter injury, glial cell activation, inflammation, and oxidative stress were assessed. RESULTS: The joint [Formula: see text] group exhibited synergistic effects on white matter injury (2.3× the additive nPM and [Formula: see text] scores) with greater loss of corpus callosum volume on T2 magnetic resonance imaging (MRI) (30% smaller than FA group). Histochemical analyses suggested potential microglial-specific inflammatory responses with synergistic effects on corpus callosum C5 immunofluorescent density and whole brain nitrate concentrations (2.1× and 3.9× the additive nPM and [Formula: see text] effects, respectively) in the joint exposure group. Transcriptomic responses (RNA-Seq) showed greater impact of [Formula: see text] than individual additive effects, consistent with changes in proinflammatory pathways. Although nPM exposure alone did not alter working memory, the [Formula: see text] cohort demonstrated impaired working memory when compared to the [Formula: see text] group. DISCUSSION: Our data suggest that nPM and CCH contribute to white matter injury in a synergistic manner in a mouse model. Adverse neurological effects may be aggravated in a susceptible population exposed to air pollution. https://doi.org/10.1289/EHP879

A13K-0336: Airborne Multi-Wavelength High Spectral Resolution Lidar for Process Studies and Assessment of Future Satellite Remote Sensing Concepts

NASA Langley recently developed the world's first airborne multi-wavelength high spectral resolution lidar (HSRL). This lidar employs the HSRL technique at 355 and 532 nm to make independent, unambiguous retrievals of aerosol extinction and backscatter. It also employs the standard backscatter technique at 1064 nm and is polarization-sensitive at all three wavelengths. This instrument, dubbed HSRL-2 (the secondgeneration HSRL developed by NASA Langley), is a prototype for the lidar on NASA's planned Aerosols- Clouds-Ecosystems (ACE) mission. HSRL-2 completed its first science mission in July 2012, the Two-Column Aerosol Project (TCAP) conducted by the Department of Energy (DOE) in Hyannis, MA. TCAP presents an excellent opportunity to assess some of the remote sensing concepts planned for ACE: HSRL-2 was deployed on the Langley King Air aircraft with another ACE-relevant instrument, the NASA GISS Research Scanning Polarimeter (RSP), and flights were closely coordinated with the DOE's Gulfstream-1 aircraft, which deployed a variety of in situ aerosol and trace gas instruments and the new Spectrometer for Sky-Scanning, Sun-Tracking Atmospheric Research (4STAR). The DOE also deployed their Atmospheric Radiation Measurement Mobile Facility and their Mobile Aerosol Observing System at a ground site located on the northeastern coast of Cape Cod for this mission. In this presentation we focus on the capabilities, data products, and applications of the new HSRL-2 instrument. Data products include aerosol extinction, backscatter, depolarization, and optical depth; aerosol type identification; mixed layer depth; and rangeresolved aerosol microphysical parameters (e.g., effective radius, index of refraction, single scatter albedo, and concentration). Applications include radiative closure studies, studies of aerosol direct and indirect effects, investigations of aerosol-cloud interactions, assessment of chemical transport models, air quality studies, present (e.g., CALIPSO) and future (e.g., EarthCARE) satellite calibration/validation, and development/assessment of advanced retrieval techniques for future satellite applications (e.g., lidar+polarimeter retrievals of aerosol and cloud properties). We will also discuss the relevance of HSRL-2 measurement capabilities to the ACE remote sensing concept

Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

Viral resistance to small molecule allosteric inhibitors of CCR5 is well documented, and involves either selection of preexisting CXCR4-using HIV-1 variants or envelope sequence evolution to use inhibitor-bound CCR5 for entry. Resistance to macromolecular CCR5 inhibitors has been more difficult to demonstrate, although selection of CXCR4-using variants might be expected. We have compared the in vitro selection of HIV-1 CC1/85 variants resistant to either the small molecule inhibitor maraviroc (MVC) or the macromolecular inhibitor 5P12-RANTES. High level resistance to MVC was conferred by the same envelope mutations as previously reported after 16–18 weeks of selection by increasing levels of MVC. The MVC-resistant mutants were fully sensitive to inhibition by 5P12-RANTES. By contrast, only transient and low level resistance to 5P12-RANTES was achieved in three sequential selection experiments, and each resulted in a subsequent collapse of virus replication. A fourth round of selection by 5P12-RANTES led, after 36 weeks, to a “resistant” variant that had switched from CCR5 to CXCR4 as a coreceptor. Envelope sequences diverged by 3.8% during selection of the 5P12-RANTES resistant, CXCR4-using variants, with unique and critical substitutions in the V3 region. A subset of viruses recovered from control cultures after 44 weeks of passage in the absence of inhibitors also evolved to use CXCR4, although with fewer and different envelope mutations. Control cultures contained both viruses that evolved to use CXCR4 by deleting four amino acids in V3, and others that maintained entry via CCR5. These results suggest that coreceptor switching may be the only route to resistance for compounds like 5P12-RANTES. This pathway requires more mutations and encounters more fitness obstacles than development of resistance to MVC, confirming the clinical observations that resistance to small molecule CCR5 inhibitors very rarely involves coreceptor switching

BMI, Diet and Female Reproductive Factors as Risks for Thyroid Cancer: A Systematic Review

Background: Thyroid cancer incidence rates have been increasing worldwide but the reason behind this is unclear. Both the increasing use of diagnostic technologies allowing the detection of thyroid cancer and a true increase in thyroid cancer incidence have been proposed. This review assesses the role of body mass index (BMI), diet, and reproductive factors on the thyroid cancer trend. Methods: Epidemiologic studies of the selected risk factors up to June 2010 were reviewed and critically assessed. Results: Among the thirty-seven studies reviewed and despite variation in the risk estimates, most papers supported a small but positive association for BMI (risk estimate range: 1.1–2.3 in males and 1.0–7.4 in females.). Among specific dietary components, there was no consistent association of thyroid cancer risk with iodine intake through fortification (risk estimate range: 0.49–1.6) or fish consumption (risk estimate range 0.6–2.2), nor with diets high in cruciferous vegetables (risk estimate range 0.6–1.9). A small number of studies showed a consistent protective effect of diets high in non-cruciferous vegetable (risk estimate range: 0.71–0.92). Among reproductive factors (pregnancy, parity, number of live births, use of prescription hormones, menstrual cycle regularity, and menopausal status), none were consistently associated with higher thyroid cancer risk. Conclusions: BMI had the strongest link to thyroid cancer risk among those examined. Detailed examinations of populationleve