C-Reactive Protein (CRP) is Associated With Chronic Pain Independently of Biopsychosocial Factors.

Inflammation is linked with chronic pain but the extent to which this relationship is associated with biopsychosocial factors is not known. We investigated relationships between blood C-reactive protein (CRP) and regional chronic pain conditions adjusting for a large range and number of potential confounders. We performed cross-sectional analyses using the UK Biobank (N = 415,567) comparing CRP in people reporting any of 9 types of regional chronic pain with pain-free controls. Using logistic regression modelling, we explored relationships between CRP and the presence of chronic pain, with demographic, socioeconomic, psychological/lifestyle factors, and medical comorbidities as covariates. CRP was higher in chronic pain at any site compared with controls (Females: median [interquartile range] 1.60 mg/L [2.74] vs 1.17 mg/L [1.87], P < .001; Males: 1.44 mg/L [2.12] vs 1.15 mg/L [1.65], P < .001). In males, associations between CRP and all types of chronic pain were attenuated but remained significant after adjustment for biopsychosocial covariates (OR range 1.08-1.49, P ≤ .001). For females, adjusted associations between CRP and pain remained significant for most chronic pain types (OR range 1.07-1.34, P < .001) except for facial pain (OR 1.04, P = .17) and headache (OR 1.02, P = .07)-although these non-significant findings may reflect reduced sample size. The significant association between CRP and chronic pain after adjustment for key biopsychosocial confounders implicates an independent underlying biological mechanism of inflammation in chronic pain. The presence of yet unknown or unmeasured confounding factors cannot be ruled out. Our findings may inform better-targeted treatments for chronic pain. PERSPECTIVE: Using a large-scale dataset, this article investigates associations between chronic pain conditions and blood C-reactive protein (CRP), to evaluate the confounding effects of a range of biopsychosocial factors. CRP levels were higher in those with chronic pain versus controls after adjusting for confounders-suggesting a possible independent biological mechanism.

Exploring the therapeutic potential of an antinociceptive and anti-inflammatory peptide from wasp venom.

Animal venoms are rich sources of neuroactive compounds, including anti-inflammatory, antiepileptic, and antinociceptive molecules. Our study identified a protonectin peptide from the wasp Parachartergus fraternus' venom using mass spectrometry and cDNA library construction. Using this peptide as a template, we designed a new peptide, protonectin-F, which exhibited higher antinociceptive activity and less motor impairment compared to protonectin. In drug interaction experiments with naloxone and AM251, Protonectin-F's activity was decreased by opioid and cannabinoid antagonism, two critical antinociception pathways. Further experiments revealed that this effect is most likely not induced by direct action on receptors but by activation of the descending pain control pathway. We noted that protonectin-F induced less tolerance in mice after repeated administration than morphine. Protonectin-F was also able to decrease TNF-α production in vitro and modulate the inflammatory response, which can further contribute to its antinociceptive activity. These findings suggest that protonectin-F may be a potential molecule for developing drugs to treat pain disorders with fewer adverse effects. Our results reinforce the biotechnological importance of animal venom for developing new molecules of clinical interest.

Design and development of novel, short, stable dynorphin-based opioid agonists for safer analgesic therapy.

Kappa opioid receptors have exceptional potential as an analgesic target, seemingly devoid of many problematic Mu receptor side-effects. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally mediated side-effects limit clinical translation. We modify endogenous dynorphin peptides to improve drug-likeness and develop safer KOP receptor agonists for clinical use. Using rational, iterative design, we developed a series of potent, selective, and metabolically stable peptides from dynorphin 1-7. Peptides were assessed for in vitro cAMP-modulation against three opioid receptors, metabolic stability, KOP receptor selectivity, desensitisation and pERK-signalling capability. Lead peptides were evaluated for in vivo efficacy in a rat model of inflammatory nociception. A library of peptides was synthesised and assessed for pharmacological and metabolic stability. Promising peptide candidates showed low nanomolar KOP receptor selectivity in cAMP assay, and improved plasma and trypsin stability. Selected peptides showed bias towards cAMP signalling over pERK activity, also demonstrating reduced desensitisation. In vivo, two peptides showed significant opioid-like antinociception comparable to morphine and U50844H. These highly potent and metabolically stable peptides are promising opioid analgesic leads for clinical translation. Since they are somewhat biased peptide Kappa agonists they may lack many significant side-effects, such as tolerance, addiction, sedation, and euphoria/dysphoria, common to opioid analgesics.

National Wastewater Reconnaissance of Analgesic Consumption in Australia.

A wastewater-based epidemiology (WBE) method is presented to estimate analgesic consumption and assess the burden of treated pain in Australian communities. Wastewater influent samples from 60 communities, representing ∼52% of Australia's population, were analyzed to quantify the concentration of analgesics used to treat pain and converted to estimates of the amount of drug consumed per day per 1000 inhabitants using pharmacokinetics and WBE data. Consumption was standardized to the defined daily dose per day per 1000 people. The population burden of pain treatment was classified as mild to moderate pain (for non-opioid analgesics) and strong to severe pain (for opioid analgesics). The mean per capita weighted total DDD of non-opioid analgesics was 0.029 DDD/day/person, and that of opioid-based analgesics was 0.037 DDD/day/person across Australia. A greater burden of pain (mild to moderate or strong to severe pain index) was observed at regional and remote sites. The correlation analysis of pain indices with different socioeconomic descriptors revealed that pain affects populations from high to low socioeconomic groups. Australians spent an estimated US $3.5 (AU $5) per day on analgesics. Our findings suggest that WBE could be an effective surveillance tool for estimating the consumption of analgesics at a population scale and assessing the total treated pain burden in communities.

Application of Mesoporous Silica Nanoparticles in Cancer Therapy and Delivery of Repurposed Anthelmintics for Cancer Therapy.

This review focuses on the biomedical application of mesoporous silica nanoparticles (MSNs), mainly focusing on the therapeutic application of MSNs for cancer treatment and specifically on overcoming the challenges of currently available anthelmintics (e.g., low water solubility) as repurposed drugs for cancer treatment. MSNs, due to their promising features, such as tunable pore size and volume, ability to control the drug release, and ability to convert the crystalline state of drugs to an amorphous state, are appropriate carriers for drug delivery with the improved solubility of hydrophobic drugs. The biomedical applications of MSNs can be further improved by the development of MSN-based multimodal anticancer therapeutics (e.g., photosensitizer-, photothermal-, and chemotherapeutics-modified MSNs) and chemical modifications, such as poly ethyleneglycol (PEG)ylation. In this review, various applications of MSNs (photodynamic and sonodynamic therapies, chemotherapy, radiation therapy, gene therapy, immunotherapy) and, in particular, as the carrier of anthelmintics for cancer therapy have been discussed. Additionally, the issues related to the safety of these nanoparticles have been deeply discussed. According to the findings of this literature review, the applications of MSN nanosystems for cancer therapy are a promising approach to improving the efficacy of the diagnostic and chemotherapeutic agents. Moreover, the MSN systems seem to be an efficient strategy to further help to decrease treatment costs by reducing the drug dose.

ß-Lactoglobulin-Modified Mesoporous Silica Nanoparticles: A Promising Carrier for the Targeted Delivery of Fenbendazole into Prostate Cancer Cells.

The clinical utilization of fenbendazole (FBZ) as a potential anticancer drug has been limited due to its low water solubility, which causes its low bioavailability. The development of a drug nanoformulation that includes the solubilizing agent as a drug carrier can improve solubility and bioavailability. In this study, Mobil Composition of Matter Number 48 (MCM-48) nanoparticles were synthesized and functionalized with succinylated ß-lactoglobulin (BLG) to prevent early-burst drug release. The BLG-modified amine-functionalized MCM-48 (MCM-BLG) nanoparticles were loaded with FBZ to produce the drug nanoformulation (FBZ-MCM-BLG) and improved the water solubility and, consequently, its anticancer effects against human prostate cancer PC-3 cells. The prepared FBZ-MCM-BLG was characterized in terms of size, zeta potential, drug loading capacity, morphology, thermal and chemical analyses, drug release, cellular uptake, cell viability, cell proliferation, production of reactive oxygen species (ROS), and cell migration. The results demonstrated that the FBZ-MCM-BLG nanoparticles have a spherical morphology with a size and zeta potential of 369 ± 28 nm and 28 ± 0.4 mV, respectively. The drug loading efficiency of the new nanoformulation was 19%. The release of FBZ was pH-dependent; a maximum cumulative release of about 76 and 62% in 12 h and a burst release of 53 and 38% in the first 0.5 h was observed at pH 1.2 and 6.8, respectively. The prepared FBZ-MCM-BLG formulation demonstrated higher cytotoxicity effects against PC-3 cells by 5.6- and 1.8-fold, respectively, when compared to FBZ and FBZ-MCM nanoparticles. The new formulation also increased the production of ROS by 1.6- and 1.2-fold and inhibited the migration of PC-3 cells when compared to the FBZ and FBZ-MCM nanoparticles, respectively. Overall, FBZ-MCM-BLG nanoparticles improved FBZ delivery to PC-3 cells and have the potential to be evaluated for the treatment of prostate cancer following a comprehensive in vivo study.

Development of Thiabendazole-Loaded Mesoporous Silica Nanoparticles for Cancer Therapy.

Thiabendazole (TBZ) is an anthelmintic drug currently studied for anticancer purposes. However, due to its low solubility, its biomedical application has been limited. Using mesoporous silica nanoparticles (MSNPs), such as Mobil Composition of Matter Number 41 (MCM-41), as a drug carrier, is a promising approach to improve the solubility of low water-soluble drugs. In the present work, we aim to develop TBZ-loaded MCM-41 (TBZ MCM-41) nanoparticles to improve the solubility and the therapeutic efficacy of TBZ against prostate cancer PC-3 cells. TBZ MCM-41 nanoparticles were synthesized with a size of 215.9 ± 0.07 nm, a spherical shape, a hexagonal array of channels, and a drug loading capacity of 19.1%. The biological effects of the nanoformulation on PC-3 cells were then evaluated using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), IncuCyte live-cell imaging system, cell migration, and reactive oxygen species (ROS) assays. The results demonstrated that TBZ was released from MCM-41 nanoparticles in a controlled manner at pH values of 1.2 and 6.8. The cell viability measurements revealed that the TBZ MCM-41 nanoparticles caused a considerable 2.8-fold increase in the cytotoxicity of TBZ (IC50 127.3 and 46 µM for TBZ and TBZ MCM-41 nanoparticles, respectively). The results of the proliferation assay were in agreement with those of the cell viability measurements, where the MCM-41 increased the cytotoxicity of TBZ in a concentration-dependent manner. Also, the TBZ MCM-41 nanoparticles were found to enhance the potency of the drug and inhibit PC-3 cell migration. In addition, the ROS assay confirmed that TBZ MCM-41 nanoparticles were approximately 15% more potent than TBZ to produce ROS. Overall, the results demonstrated that MCM-41 nanoparticles are a promising carrier to improve the therapeutic efficacy of TBZ against PC-3 cells and suggest evaluating the efficacy of the formulation in vivo.

PEGylated Mesoporous Silica Nanoparticles (MCM-41): A Promising Carrier for the Targeted Delivery of Fenbendazole into Prostrate Cancer Cells.

Low water solubility and thus low bioavailability limit the clinical application of fenbendazole (FBZ) as a potential anticancer drug. Solubilizing agents, such as Mobil Composition of Matter Number 41 (MCM) as a drug carrier, can improve the water solubility of drugs. In this study, PEGylated MCM (PEG-MCM) nanoparticles (NPs) were synthesized and loaded with FBZ (PEG-MCM-FBZ) to improve its solubility and, as a result, its cytotoxicity effect against human prostate cancer PC-3 cells. The loading efficiency of FBZ onto PEG-MCM NPs was 17.2%. The size and zeta potential of PEG-MCM-FBZ NPs were 366.3 ± 6.9 nm and 24.7 ± 0.4 mV, respectively. They had a spherical shape and released the drug in a controlled manner at pH 1.2 and pH 6.2. PEG-MCM-FBZ were found to inhibit the migration of PC-3 cells, increase the cytotoxicity effects of FBZ against PC-3 cells by 3.8-fold, and were more potent by 1.4-fold, when compared to the non-PEGylated NPs. In addition, PEG-MCM-FBZ promoted the production of reactive oxygen species by 1.3- and 1.2-fold, respectively, when compared to FBZ and MCM-FBZ. Overall, the results demonstrate that PEG-MCM-FBZ NPs enhanced FBZ delivery to PC-3 cells; therefore, they have the potential to treat prostate cancer after a comprehensive in vivo study.

Developing GLP-1 Conjugated Self-Assembling Nanofibers Using Copper-Catalyzed Alkyne-Azide Cycloaddition and Evaluation of Their Biological Activity.

Glucagon-like peptide-1 GLP-1 is a gut-derived peptide secreted from pancreatic ß-cells that reduces blood glucose levels and body weight; however, native GLP-1 (GLP-1(7-36)-NH2 and GLP-1(7-37)) have short in vivo circulation half-lives (∼2 min) due to proteolytic degradation and rapid renal clearance due to its low molecular weight (MW; 3297.7 Da). This study aimed to improve the proteolytic stability and delivery properties of glucagon-like peptide-1 (GLP-1) through modifications that form nanostructures. For this purpose, N- (NtG) and C-terminal (CtG), and Lys26 side chain (K26G) alkyne-modified GLP-1 analogues were conjugated to an azide-modified lipidic peptide (L) to give N-L, C-L, and K-26-L, respectively; or CtG was conjugated with a fibrilizing self-assembling peptide (SAP) (AEAEAKAK)3 to yield C-S, using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). N-L demonstrated the best serum stability (t1/2 > 48 h) compared to K-26-L (44 h), C-L (20 h), C-S (27 h), and the parental GLP-1(7-36;A8G)-NH2 (A8G) (19 h) peptides. Each conjugate demonstrated subnanomolar hGLP-1RA potency, and none demonstrated toxicity toward PC-3 cells at concentrations up to 1 µM. Each analogue was observed by transmission electron microscopy to form fibrils in solution. K-26-L demonstrated among the best human serum stability (t1/2 = 44 h) and similar hGLP-1RA potency (EC50 48 pM) to C-S. In conclusion, this study provided an alternative to lipid modification, i.e., fibrillizing peptides, that could improve pharmacokinetic parameters of GLP-1.

Liquid CO2 Formulated Mesoporous Silica Nanoparticles for pH-Responsive Oral Delivery of Meropenem.

Meropenem (MER) is an effective broad-spectrum antibiotic currently only available in the parenteral form requiring frequent drug preparation and administration due to its extremely poor stability. The unavailability of oral Meropenem is primarily due to its ultrapoor handling and processing stability, hydrophilic nature that inhibits the passive diffusion across the gastrointestinal (GI) epithelium, degradation in the harsh gastric environment, and GI expulsion through enterocyte efflux glycoproteins. In this regard, we have developed an oral drug delivery system that confines MER into mesoporous silica nanoparticles (MSNs i.e, MCM-41 ∼141 nm) using a novel liquid carbon dioxide (CO2) method. MER was efficiently encapsulated within pristine, phosphonate (negatively charged MSN), and amine (positively charged MSN) modified MSNs with loading capacity ranging between 25 wt % and 31 wt %. Next, the MER-MCM-NH2 particles were electrostatically coated with Eudragit S100 enteric polymer that protected MER against gastric pH (pH 1.9) and enabled site-specific delivery in the small intestine (pH 6.8). Cellular uptake results in RAW 264.7 macrophage, Caco-2, and LS174T cells confirming the efficient cellular uptake of nanoparticles in all three cell lines. More importantly, the bidirectional transport (absorptive and secretory) of MER across Caco-2 monolayer was significantly improved for both MSN-based formulations, particularly MSNs coated with a polymer (Eud-MER-MCM-NH2) where permeability was significantly enhanced (∼2.4-fold) for absorptive transport and significantly reduced (∼1.8-fold) for secretory transport. Finally, in vitro antibacterial activity [minimum inhibitory concentration (MIC)] and time-kill assay against S. aureus and P. aeruginosa showed that drug-loaded nanoparticles were able to retain antibacterial activity comparable to that of free MER in a solution at equivalent dose. Thus, Eudragit-coated silica nanoparticles could offer a promising and novel solution for oral delivery of Meropenem and other such drugs.

Oral meropenem for superbugs: challenges and opportunities.

An increase in the number of multidrug-resistant microbial strains is the biggest threat to global health and is projected to cause >10 million deaths by 2055. The carbapenem family of antibacterial drugs are an important class of last-resort treatment of infections caused by drug-resistant bacteria and are only available as an injectable formulation. Given their instability within the gut and poor permeability across the gut wall, oral carbapenem formulations show poor bioavailability. Meropenem (MER), a carbapenem antibiotic, has broad-spectrum antibacterial activity, but suffers from the above-mentioned issues. In this review, we discuss strategies for improving the oral bioavailability of MER, such as inhibiting tubular secretion, prodrug formulations, and use of nanomedicine. We also highlight challenges and emerging approaches for the development of oral MER.

Systemic inflammatory markers in neck pain: A systematic review with meta-analysis.

BACKGROUND AND OBJECTIVE: Mechanisms underpinning symptoms in non-traumatic neck pain (NTNP) and whiplash-associated disorder (WAD) are not comprehensively understood. There is emerging evidence of systemic inflammation in musculoskeletal pain conditions, including neck and back pain. The aim of this systematic review was to determine if raised blood inflammatory markers are associated with neck pain. DATABASES AND DATA TREATMENT: MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science databases were searched. Two independent reviewers identified studies for inclusion and extracted data. Meta-analysis was performed by random effects model to calculate standard mean differences (SMDs). Risk of bias of individual studies was assessed using the Newcastle-Ottawa Scale. Overall quality of evidence from meta-analysis was assessed by Grades of Recommendation, Assessment, Development and Evaluation approach. RESULTS: In total, 10 studies were included comprising 706 participants. Three studies provided data for acute WAD, two for chronic WAD, four for chronic NTNP and one for chronic mixed WAD and NTNP. Meta-analysis indicated increased interleukin 1ß (SMD: 0.84 [95% CI 0.24, 1.44], p = .01, I2  = 59%) and tumour necrosis factor α (SMD: 0.59 [0.09, 1.09], p = .02, I2  = 45%) in chronic neck pain compared to controls, but no increase in monocyte chemoattractant protein-1. Some inflammatory markers were associated with clinical variables (including pain intensity and disability). Quality of evidence was mostly low due to small samples and high heterogeneity. CONCLUSIONS: Findings imply that raised blood inflammatory markers are present in chronic neck pain, which may represent an ongoing inflammatory process in this population. SIGNIFICANCE: This systematic review advances our understanding of neck pain pathophysiology by demonstrating the presence of systemic inflammation in chronic neck pain, in the form of raised IL-1ß and TNFα. Further, numerous inflammatory markers were associated with clinical variables, including pain intensity, disability and hyperalgesia. These findings imply that systemic inflammation may contribute to mechanisms underlying neck pain.

Can wastewater analysis be used as a tool to assess the burden of pain treatment within a population?

Pain is a global health priority that is challenging to asses. Here we propose a new approach to estimating the burden of pain treatment in a population using wastewater-based epidemiology (WBE). WBE is able to quantify multiple pharmaceutical compounds in order to estimate consumption by a population. Wastewater samples collected from areas representing whole communities can be analysed to estimate the consumption of drugs used to treat pain, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. The collection and analysis of wastewater can be conducted systematically to estimate the total consumption of NSAIDs and/or opioids in the population of a catchment area and to compare changes over time within the catchment or between different catchment populations. Consumption estimates can be combined by standardising the mass consumed to Defined Daily Doses (DDD) or morphine equivalents in order to assess, the population burden of pain treatment from mild to moderate (for NSAIDs) and for strong and severe pain (for opioids). We propose this method could be used to evaluate the total pain treatment burden between locations and over time. While this concept shows promise, future studies should evaluate the applicability as a tool to measure the burden of pain receiving treatment in a community.

Baltic amber teething necklaces: could succinic acid leaching from beads provide anti-inflammatory effects?

BACKGROUND: Baltic amber teething necklaces have been popularized as a safe and natural alternative to conventional or pharmacological medicines for the management of teething pain. However, claims made by retailers regarding the efficacy and mechanism of action of these necklaces lack scientific or clinical basis. The claim most closely resembling science is the assertion that succinic acid will leach out of the beads and through the skin of the wearer and carry out anti-inflammatory and analgesic effects. The objective of the current research is to scientifically assess this claim. METHODS: Beads from necklaces were powdered for identification by infrared spectroscopy, and dissolved in sulfuric acid for quantification of succinic acid using HPLC. Succinic acid release from beads was assessed by long-term submersion of amber beads (separated according to light, medium and dark brown colour) in solvents relevant to human skin conditions. The potential for succinic acid to have anti-inflammatory effects was assessed by measuring the release of inflammatory cytokines IL-1α, IL-1ß, IL-8 and TNFα, and the inflammatory messenger PGE2, from THP-1 human macrophages after treatment with succinic acid and LPS. RESULTS: Amber teething necklaces were positively identified as Baltic amber, by comparison of the beads' infrared spectrum to the literature, and by their succinic acid content (1.5 mg per bead; 1.44% w/w). However, whole amber beads submerged in octanol or pH 5.5 phosphate buffered saline did not release any measurable succinic acid, except for the light-coloured beads in octanol which broke into tiny fragments. Additionally, treatment of macrophages with succinic acid did not reduce the release of any inflammatory cytokines measured, and displayed toxicity to the cells at high concentrations. CONCLUSIONS: While amber teething necklaces are genuine Baltic amber, we have found no evidence to suggest that the purported active ingredient succinic acid could be released from the beads into human skin. Additionally, we found no evidence to suggest that succinic acid has anti-inflammatory properties.

Glucagon-Like Peptide-1 Receptor Agonists and Strategies To Improve Their Efficiency.

Type 2 diabetes mellitus (T2DM) is increasing in global prevalence and is associated with serious health problems (e.g., cardiovascular disease). Various treatment options are available for T2DM, including the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a therapeutic peptide secreted from the intestines following food intake, which stimulates the secretion of insulin from the pancreas. The native GLP-1 has a very short plasma half-life, owning to renal clearance and degradation by the enzyme dipeptidyl peptidase-4. To overcome this issue, various GLP-1 agonists with increased resistance to proteolytic degradation and reduced renal clearance have been developed, with several currently marketed. Strategies, such as controlled release delivery systems, methods to reduce renal clearance (e.g., PEGylation and conjugation to antibodies), and methods to improve proteolytic stability (e.g., stapling, cyclization, and glycosylation) provide means to further improve the ability of GLP-1 analogs. These will be discussed in this literature review.

Solid nanoparticles for oral antimicrobial drug delivery: a review.

Most microbial infectious diseases can be treated successfully with the remarkable array of antimicrobials current available; however, antimicrobial resistance, adverse effects, and the high cost of antimicrobials are crucial health challenges worldwide. One of the common efforts in addressing this issue lies in improving the existing antibacterial delivery systems. Solid nanoparticles (SNPs) have been widely used as promising strategies to overcome these challenges. In addition, oral delivery is the most common method of drug administration with high levels of patient acceptance. Formulation into NPs can improve drug stability in the harsh gastrointestinal (GI) tract environment, providing opportunities for targeting specific sites in the GI tract, increasing drug solubility and bioavailability, and providing sustained release in the GI tract. Here, we discuss SNPs for the oral delivery of antimicrobials, including solid lipid NPs (SLNs), polymeric NPs (PNs), mesoporous silica NPs (MSNs) and hybrid NPs (HNs). We also discussed about the role of nanotechnology in IV to oral antimicrobial therapy development as well as challenges, clinical transformation, and limitations of SNPs for oral antimicrobial drug delivery.

Toxicity evaluation and nasal mucosal tissue deposition of dexamethasone-infused mucoadhesive in situ nasal gelling systems.

To demonstrate safety of a developed intranasal dexamethasone-infused in situ gelling formulation, quantification of a validated clinical biomarker indicative of cytotoxic potential using a human sinonasal explant model was first confirmed. Systematic cytotoxicity studies using the lactate dehydrogenase (LDH) detection assay revealed no elevation from baseline, in LDH levels, with tissue integrity of explanted human nasal mucosa also maintained; this was further corroborated using tissue histopathological examination. Next, with safety confirmed ex vivo, freshly excised human nasal tissue was utilised to quantify dexamethasone release from the lead sol-gel systems; this being achieved through development and validation of a HPLC-UV analytical method, which reliably quantified controlled therapeutic release and deposition into mucosal tissue. Collectively, these findings indicate promise in the safety of each excipient within the concentrations employed in the functional sol-gel system, complemented by successful and reliable drug release and deposition into human nasal mucosal tissue. These findings pave the way for application of the dexamethasone-based sol-gel system to the extended delivery of corticosteroids to nasal mucosa in the management of localised inflammatory conditions of an acute and chronic nature, such as chronic rhinosinusitis, which can be expected to benefit from controlled and extended drug delivery characteristics imparted by appropriately engineered in situ gelling systems.

Bio-Guided Fractionation of Papaya Leaf Juice for Delineating the Components Responsible for the Selective Anti-proliferative Effects on Prostate Cancer Cells.

Alternative therapies against cancer cells with minimal or no effect on healthy tissues are highly sought after. Prostate cancer (PCa) is the second most frequently diagnosed malignancy in males. The Carica papaya L. leaf extract has been traditionally used by Australian aboriginal people for anticancer properties. In this study, medium polar fraction of papaya leaf extract that had shown anti-proliferative activity in PCa cell lines in vitro, in earlier studies, was further fractionated to 28 fractions by semi-preparative HPLC. Nine of these fractions were identified to possess selective anti-proliferative responses on PCa cells in comparison to non-cancerous cells of prostate gland origin. When these nine sub-fractions were mixed in various combinations, a combination containing six of the specific fractions (FC-3) showed the best potency. FC3 inhibited the growth of BPH-1, PC-3, and LNCaP cells in a concentration-dependent manner with an IC50 value <20 µg/mL, while (unlike paclitaxel, the positive control) minimal effect was observed on the proliferation of non-cancerous, WPMY-1 and RWPE-1cells. Furthermore, synergistic interaction of FC-3 with paclitaxel was observed with combination index values in the range of 0.89-0.98 and 0.85-1.10 on PC-3 and LNCaP cells, respectively. Untargeted qualitative analysis using UHPLC (Ultra High-Performance Liquid Chromatography)-QToF (Quadrupole Time of-Flight) mass spectrometry and screening against the METLIN database indicated presence of multiple known anticancer compounds in the FC-3 extract. These outcomes show that the potent and selective anti-proliferative effects are due to a range of bio-active compounds within the medium polar fraction of papaya leaf juice.

Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile.

Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of µ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential.Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively.Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential.Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319-27. ©2018 AACR.

Sustained Simultaneous Delivery of Metronidazole and Doxycycline From Polycaprolactone Matrices Designed for Intravaginal Treatment of Pelvic Inflammatory Disease.

Poly(ɛ-caprolactone) (PCL) intravaginal matrices were produced for local delivery of a combination of antibacterials, by rapidly cooling a mixture of drug powders dispersed in PCL solution. Matrices loaded with different combinations of metronidazole (10%, 15%, and 20% w/w) and doxycycline (10% w/w) were evaluated in vitro for release behavior and antibacterial activity. Rapid "burst release" of 8%-15% of the doxycycline content and 31%-37% of the metronidazole content occurred within 24 h when matrices were immersed in simulated vaginal fluid at 37°C. The remaining drug was extracted gradually over 14 days to a maximum of 65%-73% for doxycycline and 62%-71% for metronidazole. High levels of antibacterial activity up to 89%-91% against Gardnerella vaginalis and 84%-92% against Neisseria gonorrhoeae were recorded in vitro for release media collected on day 14, compared to "nonformulated" metronidazole and doxycycline solutions. Based on the in vitro data, the minimum levels of doxycycline and metronidazole released from PCL matrices in the form of intravaginal rings into vaginal fluid in vivo were predicted to exceed the minimum inhibitory concentrations for N. gonorrhea (reported range 0.5-4.0 µg/mL) and G. vaginalis (reported range 2-12.8 µg/mL) respectively, which are 2 of the major causative agents for pelvic inflammatory disease.