Biodegradable PLGA Based Nanoparticles for Sustained Regional Lymphatic Drug Delivery

The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA–PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA–PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases

Criterion-referenced mCAFT cut-points to identify metabolically healthy cardiorespiratory fitness among adults aged 18–69 years: An analysis of the Canadian Health Measures Survey

Objective: This study aimed to develop and validate health-related criterion-referenced cutpoints for the modified Canadian Aerobic Fitness Test (mCAFT), a field-based measure to predict cardiorespiratory fitness (CRF) among adults (18–69 years). Methods: Criterionreferenced mCAFT cut-points were developed using nationally representative data from cycles 1 (2007–09) and 2 (2009–11) of the Canadian Health Measures Survey (CHMS). Receiver operating characteristic curves were used to identify age- and sex-specific cut-points for measured waist circumference, blood pressure, and high-density lipoprotein. Cut-points were validated against metabolic syndrome using a fasted sub-sample (n=1,093) from cycle 5 (2016– 17). Results: 4,967 participants (50% women) were retained for the main analyses. The mCAFT cut-points ranged from 28 to 43 mL•kg–1•min–1 (AUC: 0.60-0.87) among men, and 23 to 37 mL•kg–1•min–1 (AUC: 0.61-0.86) among women. The likelihood of meeting the new mCAFT cut-points decreased with an increase in the presence of metabolic risk factors. In total, 54% (95%CI: 42 to 67%) of Canadian adults met the new mCAFT cut-points in 2016–17. Conclusion: This study developed and validated the first health-related criterion-referenced mCAFT cutpoints for metabolic health among Canadian adults aged 18–69 years. These mCAFT cut-points may be useful in health surveillance, clinical, and public health settings. Novelty bullets We developed and validated new criterion-referenced cut-points for the modified Canadian Aerobic Fitness Test to help identify adults at potential risk of poor metabolic health. These new cut-points could help support national health surveillance efforts

Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo

Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450–550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1 mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48 h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity.Keywords: Natural products, Cardiotoxicity, Polymeric micelles, Doxorubicin, Chemosensitizatio

Iodine status during pregnancy in India and related neonatal and infant outcomes

Objective: To document iodine status in Indian pregnancies, associations with maternal diet and demographics, and offspring developmental measures. Design: Longitudinal study following mothers through pregnancy and offspring up to 24 months. Setting: Rural health-care centre (Vadu) and urban antenatal clinic (Pune) in the Maharashtra region of India. Subjects: Pregnant mothers at 17 (n 132) and 34 weeks’ (n 151) gestation and their infants from birth to the age of 24 months. Results: Median urinary iodine concentration (UIC) was 203 and 211 μg/l at 17 and 34 weeks of pregnancy, respectively (range 26–800 μg/l). Using the UIC distribution adjusted for within-person variation, extreme UIC quartiles were compared for predictors and outcomes. There was no correlation between UIC at 17 and 34 weeks, but 24 % of those with UIC in the lowest quartile at 17 weeks had UIC in the same lowest quartile at 34 weeks. Maternal educational, socio-economic status and milk products consumption (frequency) were different between the lowest and highest quartile of UIC at 34 weeks. Selected offspring developmental outcomes differed between the lowest and highest UIC quartiles (abdominal circumference at 24 months, subscapular and triceps skinfolds at 12 and 24 months). However, UIC was only a weak predictor of subscapular skinfold at 12 months and of triceps skinfold at 24 months. Conclusions: Median UIC in this pregnant population suggested adequate dietary provision at both gestational stages studied. Occasional high results found in spot samples may indicate intermittent consumption of iodine-rich foods. Maternal UIC had limited influence on offspring developmental outcomes

Naturopaths practice behaviour: provision and access to information on complementary and alternative medicines

BACKGROUND: The increasing use of complementary and alternative medicines in Australia has generated concern regarding the information on these products available to both healthcare providers and the public. The aim of this study was to examine the practice behaviours of naturopaths in relation to both the provision of and access to information on complementary and alternative medicines (CAM). METHODS: A representative sample of 300 practicing naturopaths located nationally were sent a comprehensive survey which gathered data on self reported practice behaviour in relation to the provision of information on oral CAM to clients and the information needs of the practitioners themselves RESULTS: A response rate of 35% was achieved. Most practitioners (98%) have a dispensary within their clinic and the majority of practitioners perform the dispensing themselves. Practitioners reported they provided information to clients, usually in the form of verbal information (96%), handwritten notes (83%) and printed information (75%). The majority of practitioners (over 75%) reported always giving information on the full name of the product, reason for prescribing, expected response, possible interactions and contraindications and actions of the product. Information resources most often used by practitioners included professional newsletters, seminars run by manufacturers, patient feedback and personal observation of patients. Most practitioners were positive about the information they could access but felt that more information was required in areas such as adverse reactions and safe use of CAM in children, pregnancy and breastfeeding. Most naturopaths (over 96%) were informed about adverse events through manufacturer or distributor newsletters. The barriers in the provision of information to clients were misleading or incorrect information in the media, time constraints, information overload and complex language used in printed information. The main barrier to the practitioner in information access was seen as the perceived division between orthodox and complementary medicine practitioners. CONCLUSION: Our data suggest most naturopaths were concerned about possible interaction between pharmaceuticals and CAM, and explore this area with their patients. There is scope to improve practitioners' access to information of adverse events including an increased awareness of sources of information such as the Australian Therapeutic Goods Administration (TGA) website

Decreased Prevalence of Lymphatic Filariasis among Diabetic Subjects Associated with a Diminished Pro-Inflammatory Cytokine Response (CURES 83)

Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates of sero-positivity of LF among diabetic subjects was carried out (n = 1416) as part of the CURES study. There was a significant decrease in the prevalence of LF among diabetic subjects (both newly diagnosed [5.7%] and those under treatment [4.3%]) compared to pre-diabetic subjects [9.1%] (p = 0.0095) and non-diabetic subjects [10.4%] (p = 0.0463). A significant decrease in filarial antigen load (p = 0.04) was also seen among diabetic subjects. Serum cytokine levels of the pro-inflammatory cytokines—IL-6 and GM-CSF—were significantly lower in diabetic subjects who were LF positive, compared to those who were LF negative. There were, however, no significant differences in the levels of anti-inflammatory cytokines—IL-10, IL-13 and TGF-β—between the two groups. Although a direct causal link has yet to be shown, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished pro-inflammatory cytokine response in Asian Indians with diabetes and concomitant LF

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

<p>Abstract</p> <p>Background</p> <p>BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer.</p> <p>Case Presentation</p> <p>A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat.</p> <p>Conclusions</p> <p>Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.</p

The antioxidant and antiproliferative activities of methanolic extracts from Njavara rice bran

<p>Abstract</p> <p>Background</p> <p>Free radical-induced oxidative stress is the root cause for many human diseases. Naturally occurring antioxidant supplements from plants are vital to counter the oxidative damage in cells. The main objective of the present study was to characterize the antioxidant and antiproliferative potential of rice bran extracted from an important Indian rice variety, Njavara and to compare the same with two commercially available basmati rice varieties: Vasumathi, Yamini and a non medicinal variety, Jyothi.</p> <p>Methods</p> <p>Methanolic extracts of rice bran from four varieties; Vasumathi, Yamini, Jyothi and Njavara were used to study their total phenolic and flavonoid contents, <it>in vitro </it>antioxidant activities including total antioxidant activity, scavenging of nitric oxide and 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical, reducing power and cytotoxic activity in C6 glioma cells. Correlation coefficient and regression analysis were done by using Sigmastat version 3.1 and Stata statistical package respectively.</p> <p>Results</p> <p>Rice bran methanolic extract from Njavara showed the highest antioxidant and cell cytotoxic properties compared to the other three rice varieties. IC₅₀values for scavenging DPPH and nitric oxide were in the range of 30.85-87.72 μg/ml and 52.25-107.18 μg/ml respectively. Total antioxidant activity and reducing power were increased with increasing amounts of the extract. Total phenolic and flavonoid contents were in the range of 3.2-12.4 mg gallic acid-equivalent (GAE)/g bran and 1.68-8.5 mg quercetin-equivalent (QEE)/g bran respectively. IC₅₀values of cytotoxic assay (MTT assay) were 17.53-57.78 μg/ml. Correlation coefficient and regression analysis of phenolic content with DPPH and NO scavenging, MTT (-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, total antioxidant assay and reducing power showed a highly significant correlation coefficient values (96-99%) and regression values (91-98%).</p> <p>Conclusion</p> <p>The results of the present study show that the crude methanolic extract from Njavara rice bran contains significantly high polyphenolic compounds with superior antioxidant activity as evidenced by scavenging of free radicals including DPPH and NO. Njavara extracts also showed highest reducing power activity, anti-proliferative property in C6 glioma cells. In conclusion, it is conceivable that the Njavara rice variety could be exploited as one of the potential sources for plant - based pharmaceutical products.</p