Polyethylene Sebacate-Silymarin Nanoparticles with Enhanced Hepatoprotective Activity.

The present study evaluates role of pullulan as hepatic targeting agent. Nanoparticles of silymarin (SIM) a hepatoprotective drug were prepared using polyethylene sebacate (PES) as biodegradable polymer and surface modified with pullulan. PES-SIM nanoparticles (PES-SIM NP) and PES-SIM nanoparticles surface modified with pullulan (PES-SIM-PUL) were prepared by nanoprecipitation. Nanoparticles were evaluated for hepatoprotective activity in a model of carbon-tetrachloride (CCl4) induced hepatotoxicity in rats. Pretreatment of rats with PES-SIM-NP and PES-SIM-PUL revealed reduced levels of SGOT, SGPT and ALKP compared to CCl4 treated group (p < 0.01) whereas levels of LPO and catalase were comparable to vehicle control suggesting enhanced hepatoprotection with nanoparticles. Histopathological evaluation of liver tissues also revealed better hepatoprotection with nanoparticles. Further significant decrease (p < 0.01) in levels of SGOT, SGPT and ALKP with difference PES-SIM-PUL than PES-SIM NP confirms the role of pullulan as hepatic targeting agent.

Modulation of Drug Release from Natural Polymer Matrices by Response Surface Methodology: in vitro and in vivo Evaluation.

PURPOSE: The present work aimed at challenging the efficacy of natural gums, karaya and locust bean gum, as matrix-forming polymers for the formulation of sustained-release tablets of diltiazem, a model drug. METHODS: Central design composite was adopted for the formulation and optimization of tablet formulations. The two gums have been selected as independent variables. The dependent factors chosen were the amount of drug released in 1st hour (Y1), amount of drug released after 12 h (Y2), diffusion exponent (Y3), and time for half of the total drug released (T50%) (Y4). Wet granulation approach was used for the formulation of tablets. FT-IR, DSC, in vitro dissolution, swelling-erosion investigations, SEM, and stability studies were carried out. RESULTS AND DISCUSSION: It was evident that the release pattern from the prepared formulations was significantly influenced by the quantity of gum(s) in the tablet. FT-IR and DSC results confirm drug-polymer compatibility. Polynomial equations were used for the prediction of quantitative impact of independent factors at different levels on response variables. After ANOVA analysis, the significant factors were considered for constrained optimization to get the optimized formula. The optimized formula generated by the response surface methodology was evaluated both for in vitro and in vivo properties. The optimized formula and a sustained-release marketed product were subjected to in vivo studies in rabbits and the results of the t-test demonstrated insignificant variation in pharmacokinetic parameters among the two formulations, confirming that the prepared tablet showed sustained-release profile. CONCLUSION: The results indicated that karaya and locust bean gum can be effectively used to formulate sustained-release tablets.

Human herpesvirus 8 presence and viral load are associated with the progression of AIDS-associated Kaposi's sarcoma.

OBJECTIVE: We present the largest longitudinal study to date that examines the association between Kaposi's Sarcoma (KS) disease progression and the presence and viral load of human herpesvirus 8 (HHV-8). METHODS: Ninety-six men were enrolled at HIV clinics in Atlanta, Georgia, who had KS (n = 47) or were without KS but seropositive for HHV-8. Visits occurred at 6-month intervals for 2 years at which the patient's KS status was evaluated and oral fluid and blood were collected for quantification of HHV-8 DNA and antibodies. RESULTS: The presence of HHV-8 DNA in blood was more common (P < 0.001) and the viral load higher (P < 0.001) in men with KS in comparison with men without KS. Mean HHV-8 viral loads in blood and oral fluids were associated with disease status, being highest among patients with progressing KS, intermediate among patients with stable KS, and lowest among patients with regressing KS. Consistent with our previous report high antibody titers to HHV-8 orf 65 were inversely associated with HHV-8 shedding in oral fluid. CONCLUSIONS: We observed a significant association between changes in KS disease severity and the presence and viral load of HHV-8. HHV-8 viral load in blood may provide useful information to clinicians for assessment of the risk of further disease progression in patients with KS.

Cone Beam Computerized Tomography Analysis of the Posterior and Anterior Mandibular Lingual Concavity for Dental Implant Patients.

This study was conducted to evaluate variations in and the prevalence of the lingual concavity. Images were taken between January 1, 2011, and August 31, 2015, from a total of 104 patient charts randomly selected from a private practice. These images were acquired from a single cone beam computerized tomography (CBCT) machine. The CBCTs were reviewed in cross-sectional images in both the left and right anterior incisor and posterior molar regions. These scans were classified into 1 of 3 categories-parallel, concave, or convex-based on the measurements of the level of concavity degree as well as the mandibular morphology observed. Lingual concavity characteristics including depth, angulation, and vertical location were also measured. Most of the posterior mandibular CBCT scans were classified as concave. Although there was no significant difference detected for race or gender, statistical significance was noted with regard to age, with an increase in prevalence observed at age 63 years and older. Of the 3 different morphological classifications used, the vast majority were identified as concave in the posterior mandibular regions and parallel in the anterior mandibular region. There was a significant decrease in concavity VL/height (bone loss) associated with age, which was most commonly seen in edentulous areas.

Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma.

We report asialoglycoprotein receptor (ASGPR)-targeted doxorubicin hydrochloride (Dox) nanoparticles (NPs) for hepatocellular carcinoma (HCC). Polyethylene sebacate (PES)-Gantrez® AN 119 Dox NPs of average size 220 nm with PDI < 0.62 and ∼20% Dox loading were prepared by modified nanoprecipitation. ASGPR ligands, pullulan (Pul), arabinogalactan (AGn), and the combination (Pul-AGn), were anchored by adsorption. Ligand anchoring enabled high liver uptake with a remarkable hepatocyte:nonparenchymal cell ratio of 85:15. Furthermore, Pul-AGn NPs exhibited an additive effect implying incredibly high hepatocyte accumulation. Galactose-mediated competitive inhibition confirmed ASGPR-mediated uptake of ligand-anchored NPs in HepG2 cell lines. Subacute toxicity in rats confirmed the safety of the NP groups. However, histopathological evaluation suggested mild renal toxicity of AGn. Pul NPs revealed sustained reduction in tumor volume in PLC/PRF/5 liver tumor-bearing Nod/Scid mice up to 46 days. Extensive tumor necrosis, reduced collagen content, reduction in the HCC biomarker serum α-fetoprotein (p < 0.05), a mitotic index of 1.135 (day 46), and tumor treated/tumor control (T/C) values of <0.42 signified superior efficacy of Pul NPs. Furthermore, weight gain in the NP groups, and no histopathological alterations indicated that they were well tolerated by the mice. The high efficacy coupled with greater safety portrayed Pul Dox NPs as a promising nanocarrier for improved therapy of HCC.

Sustained virologic response with short-course ribavirin and peginterferon treatment in 2 patients coinfected with HIV and HCV genotype 1.

The current recommendation for the duration of treatment of patients infected with chronic hepatitis C virus (HCV) genotype 1 is 48 weeks; however, the standard regimen of peginterferon plus ribavirin bears significant adverse effects, which make completion of treatment exceedingly difficult. Reported here are 2 cases of HIV-HCV-coinfected genotype-1 patients who discontinued treatment early (after 3 and 8 weeks) because of adverse effects yet had a sustained virologic response with undetectable HCV viral loads at follow-up.

Polyethylene sebacate doxorubicin nanoparticles: role of carbohydrate anchoring on in vitro and in vivo anticancer efficacy.

We report carbohydrate-anchored polyethylene sebacate (PES)-Gantrez® AN 119 Doxorubicin hydrochloride (Dox) nanoparticles (NPs) for enhanced anticancer efficacy. The carbohydrates Arabinogalactan (AGn), an adjuvant in anticancer chemotherapy and pullulan (Pul) reported to promote collagen synthesis, were selected as ligands. PES Dox NPs of an average size around 200 nm, greater than 20% w/w Dox loading and negative zeta potential were anchored with Pul, AGn, and Pul-AGn combination by simple incubation. Increase in particle size and zeta potential confirmed carbohydrate anchoring. FTIR confirmed ionic complexation of Dox and Gantrez® AN 119. DSC and XRD demonstrated amorphization of Dox. Higher Dox release in pH 5.5 as compared with pH 7.4 is beneficial for reduced systemic toxicity and enhanced drug release in tumors. Good in vitro serum stability and low hemolysis revealed suitability for intravenous administration. All NPs revealed circulation longevity in normal rats. Pul NPs revealed superior anticancer efficacy in vitro and an 11-fold enhancement in uptake in MCF-7 breast cancer cells. The greater efficacy in vivo is attributed to possible pullulan-mediated integrin receptor uptake and interaction with tumor collagen. Histopathology confirmed safety and suggested promise of Pul NPs in improved anticancer efficacy.

Recent advances in protein and Peptide drug delivery: a special emphasis on polymeric nanoparticles.

Proteins and peptides are widely indicated in many diseased states. Parenteral route is the most commonly em- ployed method of administration for therapeutic proteins and peptides. However, requirement of frequent injections due to short in vivo half-life results in poor patient compliance. Non-invasive drug delivery routes such as nasal, transdermal, pulmonary, and oral offer several advantages over parenteral administration. Intrinsic physicochemical properties and low permeability across biological membrane limit protein delivery via non-invasive routes. One of the strategies to improve protein and peptide absorption is by delivering through nanostructured delivery carriers. Among nanocarriers, polymeric nanoparticles (NPs) have demonstrated significant advantages over other delivery systems. This article summarizes the application of polymeric NPs for protein and peptide drug delivery following oral, nasal, pulmonary, parenteral, transder mal, and ocular administrations.

Comparative evaluation of polymeric nanoparticles of rifampicin comprising Gantrez and poly(ethylene sebacate) on pharmacokinetics, biodistribution and lung uptake following oral administration.

The present study reports the comparative pharmacokinetic evaluation and biodistribution of rifampicin (RIF) following oral administration of nanoparticles of a bioadhesive polymer, Gantrez and a hydrophobic polymer poly(ethylene sebacate) (PES). A specific objective of the study was to evaluate lung uptake of the nanoparticles following oral administration. Nanoparticles were obtained in the size range 350-450 nm with rifampicin loading of 12-14% w/w. Zeta potential confirmed colloidal stability. PES nanoparticles revealed high macrophage uptake compared to Gantrez nanoparticles, and direct correlation was observed between hydrophobicity (contact angle) and macrophage uptake (r2 -0.940). Enhanced RIF uptake with folic acid anchoring suggested folate receptor mediated uptake. RIF nanoparticles exhibited significantly higher Cmax and AUC, delayed Tmax and sustained release compared to plain RIF. More importantly the plasma concentration of RIF with the nanoparticles was significantly greater than the MIC of RIF (0.25 microng/mL) over 24 h. While gamma scintigraphy revealed higher lung accumulation of nanoparticles, the concentration with Gantrez nanoparticles was significantly higher. HPLC evaluation of lung concentration correlated with scintigraphy data. The significantly higher bioavailability and lung accumulation with Gantrez nanoparticle over PES nanoparticles was attributed mucoadhesion and high affinity of Gantrez to the Peyer's patches. Our study suggests Gantrez nanoparticles as a promising carrier for enhancing lung accumulation of drugs.

Ionic complexation as a non-covalent approach for the design of folate anchored rifampicin Gantrez nanoparticles.

The present study discloses the design of folate anchored Rifampicin-Poly methylvinylether maleic anhydride copolymer (Gantrez AN-119, Gantrez) nanoparticles (RFMGzFa) by ionic complexation. Folic acid was anchored to the preformed drug loaded nanoparticles. Folic acid was anchored in different concentration by simply varying the amount of folic acid added during preparation. RFMGzFa nanoparticles were prepared by emulsion solvent diffusion method. Gantrez AN-119 rapidly hydrolyzes in aqueous medium releasing carboxylic acid groups, to create an acidic environment. This facilitates protonation and subsequent ionic complexation of folic acid with the carboxylic groups, to enable anchoring. FTIR spectra confirmed this interaction. Infrared imaging revealed distribution of folic acid across the nanoparticle surface. Nanoparticles were obtained in the size range 350-450 nm with RFM loading of 12-14% w/w. Zeta potential confirmed colloidal stability. TEM/SEM revealed spherical morphology. RFMGzFa nanoparticles exhibited sustained release of RFM and folic acid. Folic acid showed sustained release upto 12 h, which was ion exchange mediated. A 480% enhancement in RFM uptake with RFMGzFa nanoparticles compared to 300% with RFMGz nanoparticles in-vitro, in human macrophage cell line U-937, suggested the role of folic acid in folate receptor mediated uptake. Ionic complexation represents a simple non-covalent approach for anchoring folic acid on polymeric nanoparticles of Gantrez.

"Isolation, identification, characterization and polymetallic concentrate leaching studies of tryptic soy- and peptone-resistant thermotolerant Acidithiobacillus ferrooxidans SRDSM2".

Acidithiobacillus ferrooxidans strain SRDSM2 was isolated from silica containing soil sample collected at a Rajpardi lignite mine. The strain responded to the addition of 0.5 g/L peptone and 1.0 g/L tryptone soya broth in the ferrous sulphate tryptone soya broth (ITSB) medium with 35.3% and 29.6% increase in iron oxidation rate (IOR), but decrease in the IOR at higher peptone or tryptone soya broth levels. The presence of 4 mM of zinc as zinc sulphate in the medium increased the IOR by 24.4%. Forty percent of the inoculated cells survived even after exposure at 80 °C for 120 min and showed 30% ferrous iron oxidation. The Vmax and Ks for iron oxidation by the isolate were 344.82 mg/L/h and 32.25 g/L respectively. The isolate was able to oxidized ferrous iron even in presence of 4.06 M ionic strength of medium and leached>85% copper and zinc from the polymetallic concentrate. Thus, this isolate can be used for bioextraction of metals from polymetallic concentrate.