Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins ...comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. The receptor is located not only on inflammatory cells (meningeal and peripheral macrophages) but on neuraxial glia (microglia and astrocytes), Schwann cells, fibroblasts, dorsal root ganglia, and dorsal horn neurons. Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.
Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, ...cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
Drug-eluting embolic transarterial chemoembolization (DEE-TACE) improves the overall survival of hepatocellular carcinoma (HCC), but the agents used are not tailored to HCC. Our patented liposomal ...formulation enables the loading and elution of targeted therapies onto DEEs. This study aimed to establish the safety, feasibility, and pharmacokinetics of sorafenib or regorafenib DEE-TACE in a VX2 model. DEE-TACE was performed in VX2 hepatic tumors in a selective manner until stasis using liposomal sorafenib- or regorafenib-loaded DEEs. The animals were euthanized at 1, 24, and 72 h timepoints post embolization. Blood samples were taken for pharmacokinetics at 5 and 20 min and at 1, 24, and 72 h. Measurements of sorafenib or regorafenib were performed in all tissue samples on explanted hepatic tissue using the same mass spectrometry method. Histopathological examinations were carried out on tumor tissues and non-embolized hepatic specimens. DEE-TACE was performed on 23 rabbits. The plasma concentrations of sorafenib and regorafenib were statistically significantly several folds lower than the embolized liver at all examined timepoints. This study demonstrates the feasibility of loading sorafenib or regorafenib onto commercially available DEEs for use in TACE. The drugs eluted locally without release into systemic circulation.
Nanoparticles of silver and gold have become widely researched as homogeneous catalysts for organic transformations. Silver systems have shown promising activity but are often hindered by their ...instability and difficulty in recycling. In this work we present nanoparticles of silver and gold, colloidally stabilized on aluminum oxide, and their performance as re-useable catalysts for the reduction of 4-nitrophenol. Compared with more standard citrate stabilized catalyst nanoparticles (k = 0.71 and 0.17 min−1 for Ag and Au respectively), the aluminum oxide stabilized systems are significantly more active (k = 1.82 and 0.63 min−1 for Ag and Au respectively) due to increased surface site availability. Importantly, Al2O3 supported silver nanoparticles exhibit excellent activity/re-usability as redox catalysts that are stable across a surprising variation of reaction media, including halide salts.
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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Human microdosing studies with novel drug candidates offer an opportunity to evaluate their pharmacokinetic (PK) behaviour early in drug development and ...before committing to the expense of clinical Phase I‐enabling activities.
• Such studies assume linearity of exposure with dose all the way down to a subtherapeutic dose.
• Previous studies have reported partial success in the use of this technique for assessing human PK of marketed drugs.
WHAT THIS STUDY ADDS
• The present study describes the application of the microdosing concept in early drug development for an H1 antagonist programme where having good estimates of human PK and information about the shape of the concentration–time curve was critical for compound selection.
• Microdosing data were generated for four novel compounds and one reference compound, and the data were used for advancing the compound with the most favourable PK properties.
• To our knowledge, this is the first example of the use microdosing technique for compound selection.
AIMS To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).
METHODS Five H1 receptor antagonists, namely NBI‐1, NBI‐2, NBI‐3, NBI‐4 and diphenhydramine, were administered to human volunteers as a single 0.1‐mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high‐performance liquid chromatography and accelerator mass spectroscopy.
RESULTS The median clearance (CL), apparent volume of distribution (Vd) and apparent terminal elimination half‐life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h−1, 302 l and 9.3 h, and the oral Cmax and AUC0–∞ were 0.195 ng ml−1 and 1.52 ng h ml−1, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI‐2 > NBI‐1 > NBI‐3 > diphenhydramine > NBI‐4, whereas the rank order for CL was NBI‐4 > diphenhydramine > NBI‐1 > NBI‐3 > NBI‐2.
CONCLUSIONS Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.
Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On ...the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
The recent discovery of hydrovoltaic devices for power generation has led to a rapid growth into new materials for harvesting energy specifically for this research field. Of the materials ...investigated, carbon materials have dominated, and graphene oxide (GO) has emerged as the leader. While graphite is conductive, it does not have functional groups to strongly interact with water, and highly functionalized GO forms strong interaction with water to generate necessary surface charges but does not typically have high conductivity. Herein, we report the fabrication and functionalization of a graphite-based structure, controlling the extent of oxidation to balance the effects of conductivity and functionalization to achieve high power outputs in hydrovoltaics. Devices prepared using the functionalized graphite achieve a power output of 53.3 μW/g. High power output and good film stability are key advances toward the practical application of hydrovoltaic devices for renewable energy.
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