Structure of pregnancy physiologically based pharmacokinetic (p-PBPK) model.

<p>Structure of pregnancy physiologically based pharmacokinetic (p-PBPK) model.</p

Indomethacin observed and predicted PK parameters after oral dosing in non-pregnant and pregnant subjects.

<p>* Reported values in pregnant subjects receiving chronic administration of 25mg of indomethacin four times daily.</p><p>** Reported values in non-pregnant, healthy subjects receiving chronic administration of 25mg of indomethacin three times daily.</p><p>Indomethacin observed and predicted PK parameters after oral dosing in non-pregnant and pregnant subjects.</p

Sensitivity analysis to evaluate mechanism(s) primarily contributes to differences in indomethacin levels in pregnancy.

<p>Contribution of changes in metabolism (CYP2C9 and UGT2B7 activities), plasma protein binding (PB), glomular filtration rate (GFR), and volume of distribution (V_d) to variation in C_ave (Black columns) and CL/F_ss (Grey columns) during pregnancy.</p

Simulated and observed PD effect-time profiles for indomethacin presented as % decrease in PGEM (13, 14-dihydro-15-ketoprostaglandin E2) plasma concentration vs. time after single oral administration of 25mg.

<p>The solid line represents predicted mean indomethacin profile in non-pregnant subjects. The dashed line represents predicted mean indomethacin profile in pregnant subjects. Mean observed data are overlaid for 25 mg dose in non-pregnant subjects [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref039" target="_blank">39</a>]. The green and blue shaded areas represent the 90% confidence interval for the simulated data, and error bars represent ± SD.</p

Tissue-to-Plasma Partition Coefficients (K_p) of indomethacin used in non-pregnant and pregnant (2^nd Trimester) subjects PBPK models.

<p>Tissue-to-Plasma Partition Coefficients (K_p) of indomethacin used in non-pregnant and pregnant (2^nd Trimester) subjects PBPK models.</p

Indomethacin PK parameters after oral dosing in non-pregnant subjects.

<p>* Reported values in non-pregnant, healthy subjects [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref022" target="_blank">22</a>].</p><p>**Reported values in non-pregnant subjects [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref002" target="_blank">2</a>].</p><p>Indomethacin PK parameters after oral dosing in non-pregnant subjects.</p

Physicochemical and <i>in vitro</i> data used in the PBPK model.

<p>[a] drugbank.ca; <a href="http://www.drugbank.ca/drugs/DB00328" target="_blank">http://www.drugbank.ca/drugs/DB00328</a></p><p>[b] Caco–2 effective permeability taken from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref023" target="_blank">23</a>].</p><p>[c] Renal clearance in humans taken from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref008" target="_blank">8</a>].</p><p>[d] Optimized value of <i>in vitro</i> data taken from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref009" target="_blank">9</a>] (reported values were 9.9 μM for K_M and 0.33 pmol/min/pmol CYP for V_max).</p><p>[e] Optimized value of <i>in vitro</i> data taken from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139762#pone.0139762.ref011" target="_blank">11</a>] (reported values were 17.7 μM for K_M and 229.4 pmol/min/mg protein for V_max).</p><p>* <i>f</i>_m is fraction metabolized</p><p>Physicochemical and <i>in vitro</i> data used in the PBPK model.</p

Oleocanthalic Acid, a Chemical Marker of Olive Oil Aging and Exposure to a High Storage Temperature with Potential Neuroprotective Activity

The investigation of olive oils stored for a period of 24 months under appropriate conditions (25 °C, dark place, and airtight container) led to the identification of a new major phenolic ingredient, which was named oleocanthalic acid. The structure of the new compound was elucidated using one- and two-dimensional nuclear magnetic resonance in combination with tandem mass spectrometry. The new compound is an oxidation product of oleocanthal and is found in fresh oils in very low concentrations. The concentration of oleocanthalic acid increased with storage time, while the oleocanthal concentration decreased. A similar increase of the oleocanthalic acid/oleocanthal ratio was achieved after exposure of olive oil to 60 °C for 14 days. Although the presence of an oxidized derivative of decarboxymethylated ligstroside aglycon had been reported, it is the first time that its structure is characterized. The isolated compound could induce the expression of amyloid-β major transport proteins as well as tight junctions expressed at the blood–brain barrier, suggesting that oleocanthalic acid could be beneficial against Alzheimer’s disease

Gentamicin Eluting 3D-Printed Implants for Preventing Post-Surgical Infections in Bone Fractures

A surgically implantable device is an inevitable treatment option for millions of people worldwide suffering from diseases arising from orthopedic injuries. A global paradigm shift is currently underway to tailor and personalize replacement or reconstructive joints. Additive manufacturing (AM) has provided dynamic outflow to the customized fabrication of orthopedic implants by enabling need-based design and surface modification possibilities. Surgical grade 316L Stainless Steel (316L SS) is promising with its cost, strength, composition, and corrosion resistance to fabricate 3D implants. This work investigates the possibilities of application of the laser powder bed fusion (L-PBF) technique to fabricate 3D-printed (3DP) implants, which are functionalized with a multilayered antimicrobial coating to treat potential complications arising due to postsurgical infections (PSIs). Postsurgical implant-associated infection is a primary reason for implantation failure and is complicated mainly by bacterial colonization and biofilm formation at the installation site. PLGA (poly-d,l-lactide-co-glycolide), a biodegradable polymer, was utilized to impart multiple layers of coating using the airbrush spray technique on 3DP implant surfaces loaded with gentamicin (GEN). Various PLGA-based polymers were tested to optimize the ideal lactic acid: glycolic acid ratio and molecular weight suited for our investigation. 3D-Printed PLGA-GEN substrates sustained the release of gentamicin from the surface for approximately 6 weeks. The 3DP surface modification with PLGA-GEN facilitated cell adhesion and proliferation compared to control surfaces. The cell viability studies showed that the implants were safe for application. The 3DP PLGA-GEN substrates showed good concentration-dependent antibacterial efficacy against the common PSI pathogen Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). The GEN-loaded substrates demonstrated antimicrobial longevity and showed significant biofilm growth inhibition compared to control. The substrates offered great versatility regarding the in vitro release rates, antimicrobial properties, and biocompatibility studies. These results radiate great potential in future human and veterinary clinical applications pertinent to complications arising from PSIs, focusing on personalized sustained antibiotic delivery