Preparation and Evaluation of Differently Sulfonated Styrene–Divinylbenzene Cross-linked Copolymer Cationic Exchange Resins as Novel Carriers for Drug Delivery

The differently sulfonated styrene–divinylbenzene cross-linked copolymer cationic exchange resins were prepared by oil-in-water polymerization and varied degrees of sulfonation. Several characteristics of the obtained resins were evaluated, i.e., Fourier transform infrared spectra, the ion-exchange capacity, microscopic morphology, size, and swelling. The resin characteristics were altered in relation to the degree of sulfonation, proving that differently sulfonated resins could be prepared. The behavior of chlorpheniramine (CPM) loading and in vitro release in the USP simulated gastric (SGF) and intestinal fluids (SIF) of the obtained resins were also evaluated. The CPM loaded in the resinates (drug-loaded resins) increased with the increasing degree of sulfonic group and hence the drug binding site in the employed resins. The CPM release was lower from the resins with the higher degree of sulfonic group due to the increase in the diffusive path depth. The CPM release was obviously lower in SGF than SIF because CPM, a weak base drug, ionized to a greater extent in SGF and then preferred binding with rather than releasing from the resins. In conclusion, the differently sulfonated resins could be utilized as novel carriers for drug delivery.     

Complex of Rutin with β-Cyclodextrin as Potential Delivery System

This study aimed to obtain and characterize an RU-β-CD complex in the context of investigating the possibility of changes in the solubility, stability, antioxidative and microbiological activity as well as permeability of complexated rutin as against its free form. The formation of the RU-β-CD complex via a co-grinding technique was confirmed by using DSC, SEM, FT-IR and Raman spectroscopy, and its geometry was assessed through molecular modeling. It was found that the stability and solubility of the so-obtained complex were greater compared to the free form; however, a slight decrease was observed inits antibacterial potency. An examination of changes in the EPR spectra of thecomplex excluded any reducing effect of complexation on the antioxidative activity of rutin. Considering the prospect of preformulation studies involving RU-β-CD complexes, of significance is also the observed possibility of prolongedly releasing rutin from the complex at a constant level over along period of 20 h, and the fact that twice as much complexated rutin was able topermeate compared to its free form.     

Lipophilic Drug Transfer Between Liposomal and Biological Membranes: What Does It Mean for Parenteral and Oral Drug Delivery?

This review presents the current knowledge on the interaction of lipophilic, poorly water soluble drugs with liposomal and biological membranes. The center of attention will be on drugs having the potential to dissolve in a lipid membrane without perturbing them too much. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid-based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.     

Evaluation of Matrix Tablets Based on Eudragit?E100/Carbopol?971P Combinations for Controlled Release and Improved Compaction Properties of Water Soluble Model Drug Paracetamol

The purpose of this work was to investigate the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble model drug paracetamol from Carbopol®971P NF polymer matrix tablets prepared by direct compression. The effects of the ratio of the two polymers, the total polymeric content, and the tablets mechanical strength on paracetamol release rates were investigated. Dissolution studies were conducted using USP XX Π rotating paddle apparatus at 50 rpm and 37°C at three different stages (pH 1.2, 4.8, and 6.8). Results showed that the polymers combination improved significantly the compaction properties of paracetamol tablets as evident by the higher crushing strengths (8.3 ± 0.4 Kp) compared to polymer-free tablets (3.4 ± 0.2 Kp) at intermediate compression pressure of 490 MPa. When combined with Carbopol®971P NF, Eudragit®E100 was found to be capable of extending paracetamol release for more than 12 h compared to 1 h for polymers-free tablets. The combined polymers were able to control paracetamol release in a pH independent pattern. The f2 (similarity factor) analysis showed that the ratio between the polymers and the total polymer concentration exhibited significant impact on drug release rates. In conclusion, Eudragit®E100 when combined with Carbopol®971P NF was capable of improving the compaction and sustained release properties of paracetamol. Korsmeyer–Peppas model was found to be the most suitable for fitting drug release data. The polymer combinations can potentially be used to control the release rates of highly water soluble drugs.KEY WORDS: Carbopol®971P NF, Eudragit®E100, matrix tablet, pH-independent release, sustained     

Chitosan–Sodium Lauryl Sulfate Nanoparticles as a Carrier System for the In Vivo Delivery of Oral Insulin

The present work explores the possibility of formulating an oral insulin delivery system using nanoparticulate complexes made from the interaction between biodegradable, natural polymer called chitosan and anionic surfactant called sodium lauryl sulfate (SLS). The interaction between chitosan and SLS was confirmed by Fourier transform infrared spectroscopy. The nanoparticles were prepared by simple gelation method under aqueous-based conditions. The nanoparticles were stable in simulated gastric fluids and could protect the encapsulated insulin from the GIT enzymes. Additionally, the in vivo results clearly indicated that the insulin-loaded nanoparticles could effectively reduce the blood glucose level in a diabetic rat model. However, additional formulation modifications are required to improve insulin oral bioavailability.KEY WORDS: chitosan, insulin, nanoparticles, oral delivery system, sodium lauryl sulfate     

Emulsifiers’ Composition Modulates Venous Irritation of the Nanoemulsions as a Lipophilic and Venous Irritant Drug Delivery System

In this study, a nanoemulsion (NE) system was investigated for intravenous delivery of lipophilic and venous irritant drugs. NEs were prepared to deliver diallyl trisulfide (DT) for systemic therapy of bacterial and fungal infection, egg phospholipid was chosen as the main emulsifier, and two co-emulsifiers were also incorporated, including Poloxamer 188 (P188) and Solutol HS 15 (S15). Soybean oil was used as the dispersed phases, forming stable DT NEs with small particle sizes. The venous irritation of DT NEs was evaluated by in vitro human umbilical cord endothelial cells (CRL 1730) compatibility model with the intracellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations as the indices. The intracellular ATP and GTP reduction changed with the incorporation of a variety of co-emulsifiers, which varied in a free DT concentration-dependent manner. It was deduced that the free DT concentrations of NEs containing co-emulsifiers were determined by the partition coefficient of DT between oil and surfactant buffer solution. In conclusion, NE was an appropriate delivery system for lipophilic and venous irritant drug, and optimization of the composition of emulsifiers was an effective method to alleviate the venous irritation of DT NEs.     

Clinical and Cost-Effectiveness of Insulin Delivery with V-GO® Disposable Insulin Delivery Device Versus Multiple Daily Injections in Patients with Type 2 Diabetes Inadequately Controlled on Basal Insulin

Objective: To compare two methods of delivering intensified insulin therapy (IIT) in patients with type 2 diabetes inadequately controlled on basal insulin ± concomitant antihyperglycemic agents in a real-world clinical setting.Methods: Data for this retrospective study were obtained using electronic medical records from a large multicenter diabetes system. Records were queried to identify patients transitioned to V-Go® disposable insulin delivery device (V-Go) or multiple daily injections (MDI) using an insulin pen to add prandial insulin when A1C was >7% on basal insulin therapy. The primary endpoint was the difference in A1C change using follow-up A1C results.Results: A total of 116 patients were evaluated (56 V-Go, 60 MDI). Both groups experienced significant glycemic improvement from similar mean baselines. By 27 weeks, A1C least squares mean change from baseline was -1.98% (-21.6 mmol/mol) with V-Go and -1.34% (-14.6 mmol/mol) with MDI, for a treatment difference of -0.64% (-7.0 mmol/mol; P = .020). Patients using V-Go administered less mean ± SD insulin compared to patients using MDI, 56 ± 17 units/day versus 78 ± 40 units/day (P<.001), respectively. Diabetes-related direct pharmacy costs were lower with V-Go, and the cost inferential from baseline per 1% reduction in A1C was significantly less with V-Go ($118.84 ± $158.55 per patient/month compared to $217.16 ± $251.66 per patient/month with MDI; P = .013).Conclusion: Progression to IIT resulted in significant glycemic improvement. Insulin delivery with V-Go was associated with a greater reduction in A1C, required less insulin, and proved more cost-effective than administering IIT with MDI.Abbreviations:A1C = glycated hemoglobinANCOVA = analysis of covarianceCI = confidence intervalCSII = continuous subcutaneous insulin infusionFPG = fasting plasma glucoseIIT = intensified insulin therapyLSM = least squares meanMDI = multiple daily injectionsT2DM = type 2 diabetes mellitusTDD = total daily dose     

Formulation and Release Behavior of Doxycycline–Alginate Hydrogel Microparticles Embedded into Pluronic F127 Thermogels as a Potential New Vehicle for Doxycycline Intradermal Sustained Delivery

The aim of this work was the formulation and characterization of alginate (ALG)–doxycycline (DOX) hydrogel microparticles (MPs) embedded into Pluronic F127 thermogel for DOX intradermal sustained delivery. ALG–DOX MPs were formed by adding a solution of the drug into a 1.5% polymer solution while stirring. The MPs were cross-linked by dispersion into a 1.2% CaCl₂ solution. Free MPs were characterized in terms of size, drug content, and release behavior by HPLC and UV–vis. DOX and hydrogel MPs were embedded into PF127, PF127-HPMC, and PF127-Methocel thermogels. The thermogels were characterized in terms of gelling time, morphology, and release behavior. A target release period of 4–7 days was considered optimal. The hydrogel MPs were about 20 μm in size with 90% of the population <59 μm. Drug content was about 35% (w/w). DOX released rapidly from the MPs, 90% within 2 days. An expected faster release was observed for free DOX from the thermogels with 80–90% of drug released after 3.5–4 h even in the presence of 1% HPMC or Methocel. The release was sustained after embedding the MPs into PF127 and PF127-HPMC thermogels. In particular, the PF127-HPMC thermogel showed an almost linear release, reaching 80% after 3 days and 90% up to 6 days. Although a further characterization and formulation assessment is required to optimize MP characteristics, ALG/DOX-loaded hydrogel MPs, when embedded into a PF127-HPMC thermogel, show a potential for achieving a 7-day sustained release formulation for DOX intradermal delivery.     

Delivery of Therapeutic Proteins via Extracellular Vesicles: Review and Potential Treatments for Parkinson’s Disease,Glioma, and Schwannoma

Extracellular vesicles present an attractive delivery vehicle for therapeutic proteins. They intrinsically contain many proteins which can provide information to other cells. Advantages include reduced immune reactivity, especially if derived from the same host, stability in biologic fluids, and ability to target uptake. Those from mesenchymal stem cells appear to be intrinsically therapeutic, while those from cancer cells promote tumor progression. Therapeutic proteins can be loaded into vesicles by overexpression in the donor cell, with oligomerization and membrane sequences increasing their loading. Examples of protein delivery for therapeutic benefit in pre-clinical models include delivery of: catalase for Parkinson’s disease to reduce oxidative stress and thus help neurons to survive; prodrug activating enzymes which can convert a prodrug which crosses the blood–brain barrier into a toxic chemotherapeutic drug for schwannomas and gliomas; and the apoptosis-inducing enzyme, caspase-1 under a Schwann cell specific promoter for schwannoma. This therapeutic delivery strategy is novel and being explored for a number of diseases.     

α-Acetal, ω-Alkyne Poly(ethylene oxide) as a Versatile Building Block for the Synthesis of Glycoconjugated Graft-Copolymers Suited for Targeted Drug Delivery

α-Acetal, ω-alkyne poly(ethylene oxide) was synthesized as building block of glycoconjugated poly(ε-caprolactone)-graft-poly(ethylene oxide) (PCL-g-PEO) copolymers. The alkyne group is indeed instrumental for the PEGylation of a poly(α-azido-ε-caprolactone-co-ε-caprolactone) copolymer by the Huisgen's 1,3 dipolar cycloaddition, i.e., a click reaction. Moreover, deprotection of the acetal end-group of the hydrophilic PEO grafts followed by reductive amination of the accordingly formed aldehyde with an aminated sugar is a valuable strategy of glycoconjugation of the graft copolymer, whose micelles are then potential. A model molecule (fluoresceinamine) was first considered in order to optimize the experimental conditions for the reductive amination. These conditions were then extended to the decoration of the graft copolymer micelles with mannose, which is a targeting agent of dendritic cells and macrophages. The bioavailability of the sugar units at the surface of micelles was investigated by surface plasmon resonance (SPR). The same question was addressed to nanoparticles stabilized by the graft copolymer. Enzyme linked lectin assay (ELLA) confirmed the availability of mannose at the nanoparticle surface.     

CRIM1 Complexes with ?-catenin and Cadherins,Stabilizes Cell-Cell Junctions and Is Critical for Neural Morphogenesis

In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with ß-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and ß-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions.     

Is Early Oral Feeding after Gastric Cancer Surgery Feasible? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Aim

To assess the feasibility and safety of early oral feeding (EOF) after gastrectomy for gastric cancer through a systematic review and meta-analysis based on randomized controlled trials.

Methods

A literature search in PubMed, Embase, Web of Science and Cochrane library databases was performed for eligible studies published between January 1995 and March 2014. Systematic review was carried out to identify randomized controlled trials comparing EOF and traditional postoperative oral feeding after gastric cancer surgery. Meta-analyses were performed by either a fixed effects model or a random effects model according to the heterogeneity using RevMan 5.2 software.

Results

Six studies remained for final analysis. Included studies were published between 2005 and 2013 reporting on a total of 454 patients. No significant differences were observed for postoperative complication (RR = 0.95; 95%CI, 0.70 to 1.29; P = 0.75), the tolerability of oral feeding (RR = 0.98; 95%CI, 0.91 to 1.06; P = 0.61), readmission rate (RR = 1; 95%CI, 0.30 to 3.31; P = 1.00) and incidence of anastomotic leakage (RR = 0.31; 95%CI, 0.01 to 7.30; P = 0.47) between two groups. EOF after gastrectomy for gastric cancer was associated with significant shorter duration of the hospital stay (WMD = −2.36; 95%CI, −3.37 to −1.34; P<0.0001) and time to first flatus (WMD = −19.94; 95%CI, −32.03 to −7.84; P = 0.001). There were no significant differences in postoperative complication, tolerability of oral feeding, readmission rates, duration of hospital stay and time to first flatus among subgroups stratified by the time to start EOF or by partial and total gastrectomy or by laparoscopic and open surgery.

Conclusions

The result of this meta-analysis showed that EOF after gastric cancer surgery seems feasible and safe, even started at the day of surgery irrespective of the extent of the gastric resection and the type of surgery. However, more prospective, well-designed multicenter RCTs with more clinical outcomes are needed for further validation.     

Inhibition of Aflatoxin Production and Tentative Identification of an Aflatoxin Intermediate ?Versiconal Acetate” from Treatment with Dichlorvos

In general, aflatoxin production by Aspergillus flavus and A. parasiticus was greatly reduced in vitro in the presence of the insecticide dichlorvos. Reduction in yield of the toxins was accompanied by the apperance of a previously unidentified orange pigment. Spectral analyses of the pigment and of its methylated and acetylated derivatives indicated the compound to be versiconal acetate (IV). The data suggest that IV is an intermediate in the metabolic cycle that may terminate in the production of aflatoxin or of the versicolorins, or both. Dichlorvos apparently inhibits biosynthesis of the difurano ring structure common to the aflatoxins and the versicolorins.     

Phytotoxicity of Citric Acid and Tween® 80 for Potential Use as Soil Amendments in Enhanced Phytoremediation

Enhanced phytoremediation adding biodegradable amendments like low molecular weight organic acids and surfactants is an interesting area of current research to overcome the limitation that represents low bioavailability of pollutants in soils. However, prior to their use in assisted phytoremediation, it is necessary to test if amendments per se exert any toxic effect to plants and to optimize their application mode. In this context, the present study assessed the effects of citric acid and Tween® 80 (polyethylene glycol sorbitan monooleate) on the development of alfalfa (Medicago sativa) plants, as influenced by their concentration and frequency of application, in order to evaluate the feasibility for their future use in enhanced phytoremediation of multi-contaminated soils. The results showed that citric acid negatively affected plant germination, while it did not have any significant effect on biomass or chlorophyll content. In turn, Tween® 80 did not affect plant germination and showed a trend to increase biomass, as well as it did not have any significant effect on chlorophyll levels. M. sativa appeared to tolerate citric acid and Tween® 80 at the tested concentrations, applied weekly. Consequently, citric acid and Tween® 80 could potentially be utilized to assist phytoremediation of contaminated soils vegetated with M. sativa.     

Lose weight with traditional chinese medicine? Potential suppression of fat mass and obesity-associated protein

Overweight and obesity are common health problems in modern society, particularly in developed countries. Excessive body mass has been linked to numerous diseases, such as cardiovascular diseases, diabetes, and cancer. Fat mass and obesity-associated protein (FTO) activity have direct impact on food intake and results in obesity. Inhibition of FTO activity may cause weight loss and reduce obese-linked health risks. We investigated the potential weight loss effects of traditional Chinese medicine (TCM), particularly by inhibiting FTO functions. Molecular docking was performed to screen TCM compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw). Three candidates were identified that contained either a tetrahydropyridine group or potent electronegative phenol group in the structure scaffold. Molecular dynamics simulation analysis of the docking poses of each complex indicated stabilizing trends in the protein-ligand complex movements. In addition, the number of hydrogen bonds increased throughout the 20 ns simulation. These results suggest that these TCM candidates could be potential FTO inhibitors through competitive inhibition.     

Discovery of Dihydrochalcone as Potential Lead for Alzheimer’s Disease: In Silico and In Vitro Study

By the virtual screening method we have screened out Dihydrochalcone as a top-lead for the Alzheimer’s disease using the database of about 32364 natural compounds. The binding affinity of this ligand to amyloid beta (A) fibril has been thoroughly studied by computer simulation and experiment. Using the Thioflavin T (ThT) assay we have obtained the inhibition constant IC50 M. This result is in good agreement with the estimation of the binding free energy obtained by the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulation with the force field CHARMM 27 and water model TIP3P. Cell viability assays indicated that Dihydrochalcone could effectively reduce the cytotoxicity induced by A. Thus, both in silico and in vitro studies show that Dihydrochalcone is a potential drug for the Alzheimers disease.