Addressing the Osteoporosis Problem-Multifunctional Injectable Hybrid Materials for Controlling Local Bone Tissue Remodeling.

Novel multifunctional biomimetic injectable hybrid systems were synthesized. The physicochemical as well as biological in vitro and in vivo tests demonstrated that they are promising candidates for bone tissue regeneration. The hybrids are composed of a biopolymeric collagen/chitosan/hyaluronic acid matrix and amine group-functionalized silica particles decorated with apatite to which the alendronate molecules were coordinated. The components of these systems were integrated and stabilized by cross-linking with genipin, a compound of natural origin. They can be precisely injected into the diseased tissue in the form of a viscous sol or a partially cross-linked hydrogel, where they can serve as scaffolds for locally controlled bone tissue regeneration/remodeling by supporting the osteoblast formation/proliferation and maintaining the optimal osteoclast level. These materials lack systemic toxicity. They can be particularly useful for the repair of small osteoporotic bone defects.

The Tunicate Metabolite 2-(3,5-Diiodo-4-methoxyphenyl)ethan-1-amine Targets Ion Channels of Vertebrate Sensory Neurons.

Marine tunicates produce defensive amino-acid-derived metabolites, including 2-(3,5-diiodo-4-methoxyphenyl)ethan-1-amine (DIMTA), but their mechanisms of action are rarely known. Using an assay-guided approach, we found that out of the many different sensory cells in the mouse dorsal root ganglion (DRG), DIMTA selectively affected low-threshold cold thermosensors. Whole-cell electrophysiology experiments using DRG cells, channels expressed in Xenopus oocytes, and human cell lines revealed that DIMTA blocks several potassium channels, reducing the magnitude of the afterhyperpolarization and increasing the baseline intracellular calcium concentration [Ca2+]i of low-threshold cold thermosensors. When injected into mice, DIMTA increased the threshold of cold sensation by >3 °C. DIMTA may thus serve as a lead in the further design of compounds that inhibit problems in the cold-sensory system, such as cold allodynia and other neuropathic pain conditions.

Long-lasting renewable antibacterial porous polymeric coatings enable titanium biomaterials to prevent and treat peri-implant infection.

Peri-implant infection is one of the biggest threats to the success of dental implant. Existing coatings on titanium surfaces exhibit rapid decrease in antibacterial efficacy, which is difficult to promisingly prevent peri-implant infection. Herein, we report an N-halamine polymeric coating on titanium surface that simultaneously has long-lasting renewable antibacterial efficacy with good stability and biocompatibility. Our coating is powerfully biocidal against both main pathogenic bacteria of peri-implant infection and complex bacteria from peri-implantitis patients. More importantly, its antibacterial efficacy can persist for a long term (e.g., 12~16 weeks) in vitro, in animal model, and even in human oral cavity, which generally covers the whole formation process of osseointegrated interface. Furthermore, after consumption, it can regain its antibacterial ability by facile rechlorination, highlighting a valuable concept of renewable antibacterial coating in dental implant. These findings indicate an appealing application prospect for prevention and treatment of peri-implant infection.

Trends and characteristics associated with dietary triggers and psychological distress in patients with irritable bowel syndrome: a cross-sectional study.

OBJECTIVE: Diet, visceral sensitivity, and psychological distress play an important role in Irritable Bowel Syndrome (IBS). This study focused on the relation between IBS severity, foods, visceral sensitivity, and anxiety/depression. PATIENTS AND METHODS: Patients with IBS were investigated through (1) IBS-symptoms severity score (SSS), (2) self-reported food intolerance, (3) visceral sensitivity index (VSI), and (4) Hospital Anxiety and Depression Scale (HADS). Seventy-seven patients agreed to participate in the survey. Of them, 64 (83%) showed IBS according to Rome IV criteria and were included in the final analysis. Patients with IBS-D were 30 (47%), with IBS-C 27 (42%), and with IBS-M 7 (11%). RESULTS: Fifty-eight patients (90%) considered at least one foodstuff as IBS trigger. Amine-rich foods represented a symptom trigger for 77% of patients, those with lectin for 70%, IACs by 48%, and capsaicin by 37%. Overweight was significantly associated with amine-rich foods (p=0.015), age >45 years (p=0.001) and non-smoking condition (p=0.033) with lectin-rich foods, male gender (p=0.005) and overweight (p=0.027) with capsaicin-containing foods. A positive VSI score was found in 59% of patients, and non-smoking condition was significantly associated (OR 10.03; p=0.009). No factors were associated with a positive HADS score, shown by 80% of patients. Severe IBS was shown by 63% of patients, being amine-rich foods (p=0.024), overweight (p=0.020), and female gender (p=0.029) independent risk factors while marriage/cohabiting a protective one (p=0.038). Amine-rich foods are an independent risk factor for severe IBS, along with overweight and female gender. CONCLUSIONS: Clinicians should pay more attention to self-reported food intolerance in IBS patients. A personalized therapy including dietary advice as part of treatment could be of great benefit.

In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines.

PURPOSE: To advance physiologically-based pharmacokinetic modelling of xenobiotic metabolism by integrating metabolic kinetics with percutaneous absorption. METHOD: Kinetic rate equations were proposed to describe the metabolism of a network of reaction pathways following topical exposure and incorporated into the diffusion-partition equations of both xenobiotics and metabolites. The published ex vivo case study of aromatic amines was simulated. Diffusion and partition properties of xenobiotics and subsequent metabolites were determined using physiologically-based quantitative structure property relationships. Kinetic parameters of metabolic reactions were best fitted from published experimental data. RESULTS: For aromatic amines, the integrated transdermal permeation and metabolism model produced data closely matched by experimental results following limited parameter fitting of metabolism rate constants and vehicle:water partition coefficients. The simulation was able to produce dynamic concentration data for all the dermal layers, as well as the vehicle and receptor fluid. CONCLUSION: This mechanistic model advances the dermal in silico functionality. It provides improved quantitative spatial and temporal insight into exposure of xenobiotics, enabling the isolation of governing features of skin. It contributes to accurate modelling of concentrations of xenobiotics reaching systemic circulation and additional metabolite concentrations. This is vital for development of both pharmaceuticals and cosmetics.

Pharmacodynamics and pharmacokinetics of DWP14012 (fexuprazan) in healthy subjects with different ethnicities.

BACKGROUND: DWP14012 (fexuprazan), a novel potassium-competitive acid blocker, is under development for the treatment of acid-related disorders. AIMS: To compare the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of DWP14012 among healthy subjects of Korean, Caucasian and Japanese descent. METHODS: A randomised, double-blind, placebo-controlled, single- and multiple-dose study was conducted. Ten subjects in each dose group (40, 60 or 80 mg for Koreans; 40 or 80 mg for Caucasians; 20, 40 or 80 mg for Japanese) were randomly assigned to DWP14012 or a placebo. Twenty-four-hour intragastric pH measurements and serial blood samples were collected for PK/PD evaluation. The PK/PD parameters were compared between each ethnicity. RESULTS: The extent of gastric acid suppression was similar among the ethnicities; the mean percentages of time that the intragastric pH was above 4 after multiple doses of 40 mg in the Korean, Caucasian and Japanese subjects were 64.3%, 62.8% and 70.3%, respectively, and the corresponding values for the 80 mg dose were 94.8%, 90.6% and 90.6% respectively. The changes in serum gastrin were not clinically significant between all three ethnicities. The systemic exposure of DWP14012 was similar between the three ethnicities after the 40 mg doses but slightly lower in Caucasian and Japanese subjects after the 80 mg doses. Gastric acid suppression by DWP14012 showed a clear exposure-response relationship in the three ethnicities. CONCLUSIONS: Gastric acid suppression by DWP14012 was similar among the Korean, Caucasian and Japanese subjects in this study, and the PK, PK-PD relationships and safety were also similar among the three ethnicities. DWP14012 could be used without consideration of ethnicity.

Hyaluronic acid derivative-modified nano-structured lipid carrier for cancer targeting and therapy.

To reduce the problems of poor solubility, high in vivo dosage requirement, and weak targeting ability of paclitaxel (PTX), a hyaluronic acid-octadecylamine (HA-ODA)-modified nano-structured lipid carrier (HA-NLC) was constructed. HA-ODA conjugates were synthesized by an amide reaction between HA and ODA. The hydrophobic chain of HA-ODA can be embedded in the lipid core of the NLC to obtain HA-NLC. The HA-NLC displayed strong internalization in cluster determinant 44 (CD44) highly expressed MCF-7 cells, and endocytosis mediated by the CD44 receptor was involved. The HA-NLC had an encapsulation efficiency of PTX of 72.0%. The cytotoxicity of the PTX-loaded nanoparticle HA-NLC/PTX in MCF-7 cells was much stronger than that of the commercial preparation Taxol®. In vivo, the HA-NLC exhibited strong tumor targeting ability. The distribution of the NLCs to the liver and spleen was reduced after HA modification, while more nanoparticles were aggregated to the tumor site. Our results suggest that HA-NLC has excellent properties as a nano drug carrier and potential for in vivo targeting.

Development of amine-functionalized superparamagnetic iron oxide nanoparticles anchored graphene nanosheets as a possible theranostic agent in cancer metastasis.

The major objective of the present investigation was to assess the targeting potential of a designed system for breast cancer at metastatic phases with imaging ability. In a nutshell, we have developed surface-engineered graphene oxide (GO) nanosheets by covalent linking with amine-functionalized iron oxide nanoparticles (IONPs) (GOIOIs). Gefitinib (Gf) was selected as a model drug and entrapped in between exfoliated GO sheets (GOIGF) via π-π* stacking before functionalization with IONPs. Preliminary characterization of GO, IONPs, GOIOI, and GOIGF was performed using UV-visible and Fourier transform infrared spectroscopy. Scanning and transmission electron microscopy studies confirmed successful surface engineering of GO with IONPs. The in vitro drug release study demonstrated sustained release of Gf. The magnetic behavior of IONPs and GOIOI demonstrated a sigmoidal-shaped hysteresis loop with superparamagnetic properties. The in vitro cell cytotoxicity assay was carried out on MDA-MB-231 breast cancer adenocarcinoma cell lines. The cell cytotoxicity assay showed 61.18% inhibition of cell growth with 30 ppm concentration containing 64% of the drug, whereas 100% of the pure drug revealed only 56% of inhibition. In the near future, GOIOI could be tailored further for theranostic research, especially for metastatic cancers. Graphical abstract.

Doneness preferences, meat and meat-derived heterocyclic amines intake, and N-acetyltransferase 2 polymorphisms: association with colorectal adenoma in Japanese Brazilians.

Intake of heterocyclic amines (HCAs) and other mutagenic compounds formed during cooking has been hypothesized to be responsible for the positive association observed between red meat and colorectal cancer. We evaluated whether well-done/very well-done preferences for various meat and fish items, higher intakes of meat and fish, and meat-derived and fish-derived HCA are associated with the risk of colorectal adenoma (CRA) in a Japanese-Brazilian population. We selected 302 patients with adenoma and 403 control individuals who underwent total colonoscopy between 2007 and 2013, and collected information on aspects of meat intake using a detailed questionnaire. We also estimated HCA intake of the study participants using an HCA database that matched the cooking methods of this population. Latent class analysis on the basis of response to doneness preferences for different cooking methods of commonly consumed meat and fish items identified four distinct subgroups. Compared with the subgroup characterized by a preference for rare/medium well-done cooking for most meat and fish items, the odds ratio of CRA for the well-done/very well-done preference subgroup was 1.19 (95% confidence interval: 0.51-2.75). High intake of mixed-meat dishes was suggestively associated inversely with CRA, whereas a high intake of poultry was associated positively with CRA. No clear association with intake of total or specific HCAs and no effect modification by N-acetyltransferase 2 acetylation genotype were observed. We found no statistically significant associations between meat and HCA intake and CRA. These findings do not support a positive association between meat and meat-derived HCA intake and the risk of CRA.

Reconstructed chitosan with alkylamine for enhanced gene delivery by promoting endosomal escape.

Poor buffering capacity of chitosan (CS) results in insufficient intracellular gene release which poses the major barrier in gene delivery. Herein, we reconstructed pristine CS with propylamine (PA), (diethylamino) propylamine (DEAPA), and N, N-dimethyl- dipropylenetriamine (DMAMAPA) to obtain a series of alkylamine-chitosan (AA-CS). The introduction of multiple amino groups with rational ratios functionally enhance the buffering capacity of AA-CS, among which DMAPAPA-CS showed buffering capacity of 1.58 times that of chitosan. The reconstructed AA-CS functionally enhance the ability of gene binding and endosomal escape. It was observed that the DMAPAPA-CS/pDNA complexes exhibit a notable gene delivery efficiency, which promotes the functionalization of loaded pDNA. Importantly, the in vivo delivery assay reveals that the deep penetration issue can be resolved using DMAPAPA-CS gene delivery vector. Finally, the DMAPAPA-CS is applied to deliver the therapeutic p53 gene in A549 bearing mice, showing efficient therapeutic potential for cancer.

Supramolecular amphiphiles of Beta-cyclodextrin and Oleylamine for enhancement of vancomycin delivery.

The global threat of antimicrobial resistant strains calls for innovative strategies to utilize nano drug delivery systems to enhance the delivery of antibiotics, thus reducing the development of resistance. Supramolecular amphiphiles that can self-assemble into nanostructures are one such nano delivery system, that are showing potential for effective drug delivery. The aim of this study was to synthesize and formulate a novel sugar-based cationic amphiphile (BCD-OLA) derivative from a Beta-cyclodextrin (BCD) head and long C18 carbon chain with a terminal amine; oleylamine (OLA), using inclusion complexation for application in antibiotic delivery. A suspension method was used for preparing the BCD-OLA amphiphile, which was then utilized for the formulation of nanovesicles. The complexation of BCD-OLA was confirmed by FTIR, 1H NMR, 2D NMR NOESY spectrum and molecular dynamic (MD) simulations. Thereafter, biosafety was evaluated using the in vitro MTT cytotoxicity assay. Size, zeta potential (ZP), polydispersity index (PDI), entrapment efficiency, in vitro drug release and antimicrobial activity of BCD-OLA-loaded nanovesicles was also evaluated. MD of the BCD-OLA simulation showed that the mechanism responsible for amphiphile formation was through hydrophobic inclusion of OLA in BCD. MTT results showed cell viability of 75-100%, thus affirming biosafety of BCD-OLA complex. TEM images showed the self-assembled structures to be vesicles. The formulated nanovesicles size was shown to be 125.1 ± 8.30 nm with a PDI of 0.231 ± 0.05, and ZP of 19.3 ± 9.20mv. The encapsulation efficiency of vancomycin was 40.2 ± 4.5%. Vancomycin release from the nanovesicles was found to be sustained, with an 80% release over a 48 h period. The in vitro antibacterial test showed that the BCD-OLA had a 2- and 4-fold lower MIC against Staphylococcus aureus (SA) and Methicillin-resistant Staphylococcus aureus (MRSA), respectively, compared to bare vancomycin. Further, intracellular and macrophage studies showed that the system had a 459-fold reduction of intracellular bacteria using infected human embryotic kidney cells (HEK), and an 8-fold reduction in infected macrophages, contrast with bare vancomycin. These discoveries affirmed the potential of the BCD-OLA complex as a promising biosafe effective nanocarrier for antibiotic delivery.

Effectiveness of antimicrobial gels on gingivitis during fixed orthodontic treatment: A systematic review and meta-analysis.

OBJECTIVE: The present study was aimed to assess the effectiveness of antimicrobial gels along with conventional tooth brushing to improve gingival health in patients undergoing fixed orthodontic treatment. MATERIALS AND METHODS: All randomized and non-randomized clinical trials done on human subjects were explored in major health science databases (PubMed, CINAHL Plus, EBSCO Dent & Oral Sciences and Cochrane). An additional manual search was done on Google Scholar and on www.clinicaltrials.gov to identify any grey literature and unpublished data. Date of publication was not restricted during the data search. The assessment of risk of bias was done using the Cochrane Collaboration's Risk of Bias assessment tool. The meta-analysis was done using Review Manager Version 5.3.5 to analyse probing depth to be in two and four-week follow-up. This systematic review is reported according to the PRISMA statement and registered at PROSPERO (CRD42018084530). RESULTS: The electronic database search yielded 3733 records; hand search identified 14 articles meeting the selection criteria which were included in the qualitative data synthesis. Significant improvement in gingivitis has been reported using antioxidant-essential oil gel, cervitec gel (0.2% chlorhexidine), 2% chlorhexidine gel, amine fluoride gel, and 0.4% stannous fluoride gel with>98% availability of Sn+2 ions. Three articles with probing depth as comparable parameter were used for quantitative analysis. At the two and four-week follow-up, overall insignificant differences were observed in the antimicrobial gel group compared to the control group with regard to probing depth. CONCLUSIONS: The use of antioxidant-essential oil gel, amine fluoride gel, 0.4% stannous fluoride gel (98% availability of Sn+2) and 2% chlorhexidine gel resulted in significant improvement in gingivitis. However, probing depth in follow-up visits showed no significant difference between antimicrobial gel and control group.

In vitro evaluation of stearylamine cationic nanoemulsions for improved ocular drug delivery.

Oil-in-water nanoemulsions (NEs) represent one of the formulation approaches to improve eye-related bio-availability of lipophilic drugs. The potential of cationic NEs is pronounced due to the electrostatic interaction of positively charged droplets with negatively charged mucins present in the tear film, providing prolonged formulation residence at the ocular surface. The aim of this study was to develop a cationic ophthalmic NE with cationic lipid stearylamine (SA) as a carrier of a positive charge. The addition of a nonionic surfactant provided the dual electro-steric stabilization of NEs and enabled tuning of SA concentration to achieve an optimal balance between its interaction with mucins and biocompatibility. Physicochemical characterization, stability profile, in vitro mucoadhesion study and biocompatibility study employing 3D HCE-T cell-based model of corneal epithelium pointed out the NE with 0.05 % (m/m) SA as the leading formulation. Minimizing SA content while retaining droplet/mucin interactions is of great importance for efficacy and safety of future ophthalmic drug products.

Clinical effect of stannous fluoride and amine fluoride containing oral hygiene products: A 4-year randomized controlled pilot study.

This 4-year randomized controlled trial (RCT) aimed at investigating whether routine home use of both a SnCl2/AmF/NaF-containing mouth rinse and toothpaste has a preventive effect on oral health. Fifty-four test subjects were examined in biannual intervals. The primary endpoint "dental erosion" was determined by the Basic Erosive Wear Examination (BEWE). The secondary endpoints were "saliva pH", "dentin hypersensitivity" generated by Visual Analogue Scale (VAS), and "discoloration" measured by the Lobene Stain Index (LSI). A mixed model for repeated measures (MMRM) was used to analyze the primary endpoint "dental erosion". Primary analysis showed a significant intervention effect of the SnCl2/AmF/NaF-containing test product (p1 = 0.0242). This result was confirmed by two additional MMRM-based sensitivity analyses. Comparison of all models showed "dental erosion" values of the intervention group  below values of the control group. Discoloration of the teeth was significantly higher in the intervention than in the control group at all time points. Saliva pH and dentin hypersensitivity were not significantly different between groups over four years. In summary, this RCT is the first to indicate a possible preventive effect of SnCl2/AmF/NaF-containing oral hygiene products on dental erosion over a follow-up period of four years.

Multifunctional drug carrier based on PEI derivatives loaded with small interfering RNA for therapy of liver cancer.

Gene therapy strategies for liver cancer have broad application prospects but still lack a stable and efficient delivery vehicle. To overcome this obstacle, we designed a multifunctional gene delivery vector, sTPssOLP, which was based on oleylamine (OA)-modified disulfide-containing polyethylenimine (PEI) and incorporated into lipids to prepare a lipid nanoparticle. sTPssOLP consisted of the core of PEI derivative and cationic lipids bound to siRNA. The modified polyethylene glycol (PEG) and transferrin (Tf) were partially embedded in the phospholipid bilayer through the lipid and the other as the outer shell. The aim was to use the redox responsiveness of disulfide to trigger siRNA release in cytoplasm to enhance transfection efficiency. Pegylated lipids and Tf focus on increasing cycle life in the body and increasing accumulation at the tumor site of the carrier. In addition, two vectors were prepared as controls, one based on a PEI derivative containing no disulfide bond (POLP) and the other on the surface of the carrier not linked to Tf (PssOLP). PEI derivatives effectively avoid the toxicity problems caused by the use of PEI alone (25 kDa). Meanwhile, it was confirmed by gel retardation experiments that in the presence of dithiothreitol (DTT), the disulfide bond can indeed be reduced and the siRNA entrapped in the vector can be released. Both HepG2 and SMMC had significant uptake of sTPssOLP. The results of intracellular and lysosomal co-localization indicated that sTPssOLP achieved lysosomal escape. RT-PCR and Western blot results also confirmed that sTPssOLP had the best gene silencing activity. In vivo, the tumor inhibition rate of sTPssOLP in nude mice carrying HepG2 xenografts was 56%, which was significantly greater than that of the saline control group. In vivo imaging results showed that fluorescently labeled siRNA loaded in sTPssOLP was able to deliver more to the tumor site. At the same time, it was observed that sTPssOLP did not show significant damage to normal tissues. Therefore, this multifunctional gene delivery vector warrants further investigation.

Aminas cuaternarias para desinfección hospitalaria / Quaternary amines for hospital disinfection

INTRODUCCIÓN: La limpieza de superficies duras en las habitaciones de los hospitales es fundamental para reducir las infecciones asociadas con la atención médica. La descontaminación es uno o más procedimientos que resultan en una falta de patógenos residuales. Si bien la desinfección no elimina completamente el número de microorganismos, los reduce de forma significativa, de manera que es poco probable que el objeto cause infección cuando es usado. LA TECNOLOGÍA: El desinfectante marca Surfanios ® contiene N-(3-aminopropil)-N-dodecilpropano-1,3-diamina (NoCAS 2372-82-9: 51 mg/g), cloruro de didecildimetilamonio (NoCAS 7173-51-5: 25 mg/g). Las aminas cuaternarias son sólidos que se disuelven en soluciones líquidas. METODOLOGÍA: Para responder a las preguntas de eficacia y seguridad se realizó una búsqueda bibliográfica no sistemática a cargo de dos investigadores en forma independiente. Se priorizó la búsqueda de revisiones sistemáticas, meta-análisis, Informes de evaluación de Tecnologías Sanitarias y Guías de Práctica Clínica basadas en la evidencia. Se buscó en Cochrane, Medline, Lilacs, Tripdatabase, Epistemonikus, la base de datos de la OMS y sitios específicos de agencias de evaluación de tecnologías sanitarias. METODOLOGÍA DE COSTOS: Si se considera el uso de la amina cuaternaria para la desinfección de camas hospitalarias y que el sistema cuenta con 1100 camas, el consumo promedio estimado sería de 150 l, 30 bidones de 5 l, cada uno con un costo unitario de alrededor de $6000, el costo anual de compra sería de alrededor de $200.000, con alta dependencia de valor de la divisa estadounidense, dado que se trata de un produto importado. Es importante considerar que la experiencia muestra que una vez aceptada la incorporación de uma tecnología, es común su progresiva ampliación de uso para otras finalidades. En este caso, por ejemplo, podría expandirse su utilización a la desinfección de superficies generales, como pisos y mamparas, lo que incrementaría mucho la estimación de cantidades utilizadas. También es de destacar, que existen en el mercado otros desinfectantes hospitala rios de un solo passo (lauril éter sulfato de sodio o SLES (sodium lauryl ether sulfate), peróxido de hidrogeno con alcohol, otras aminas cuaternarias), que podrían ser considerados como alternativas al hipoclorito de sodio. RESULTADOS: No se encontró bibliografía o recomendaciones técnicas que i ndiquen una eficacia superior de la aminas cuaternarias por sobre el hipoclorito de sodio u otros desinfectantes hospitalarios, como tampoco evaluaciones de impacto organizacional respecto a mejoras en los tiempos de disponibilidad de camas o disminución de la carga horaria del trabajo de desinfección. Numerosos artículos de revisión no sistemática enfatizan el hecho que en desinfección hospitalaria, las decisiones sobre que producto usar están más basadas en opinión que en evidencia. RECOMENDACIÓN FINAL: Amina cuaternaria marca Surfanios® para desinfección de unidad del paciente Sentido de la Recomendación: No se recomienda su incorporación Fuerza de la Recomendación: Débil. Se recomienda que se desarrolle una guía de desinfección hospitalaria a nivel provincia l, a fin de optimizar los procedimientos, el personal que de los debe realizar y los productos a utilizar en cada caso.

Efficient weapon for protracted warfare to malaria: A chondroitin sulfate derivates-containing injectable, ultra-long-lasting meshy-gel system.

Progress at elimination of malaria is limited by the challenges of reaching large rural population and ensuring patient adherence to adequate pharmacologic treatment. In the present study, a novel material (octadecylamine modified chondroitin sulfate) was synthesized, to fabricate a long acting release meshy gel system as an efficient weapon for protracted warfare to malaria. Ivermectin loaded meshy gels (IVM-MG) composed of different amount of phospholipids, triglyceride and modified chondroitin sulfate were formulated. They were in aqueous state with low viscosity before injection, but rapidly turned into gel state with significantly increased viscosity upon exposure to an aqueous environment after injection. In vitro study proved a sustained released effect in different releasing media. In vivo study showed no irritation at injection site and slowly drug release over a 30-day release period in rat model. Among the three IVM-MG formulations, IVM-MG-3 with the highest amount of octadecylamine modified chondroitin sulfate presented the highest viscosity increase after solution-gel transition, the least initial burst release, and the longest sustained release effect over 30 days in rat model. Furthermore, by using mathematical models, IVM-MG system could boost the efficacy of mass drug administration toward malaria elimination goals. Meshy gel systems for long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases of which treatment adherence is essential for their efficacy.

The activity of encapsulated meglumine antimoniate in stearylamine-bearing liposomes against cutaneous leishmaniasis in BALB/c mice.

Topical treatment of cutaneous leishmaniasis has demonstrated appropriate alternative for reducing toxicity of conventional treatments, improving patients' compliance and reducing treatment costs. Furthermore, outbreak of cutaneous leishmaniasis in war and conflict zones emerges finding an effective, economical and user-friendly treatment. In the context of liposomal topical drug delivery, we developed and characterized meglumine antimoniate (MA) loaded liposomes and investigated their effectiveness in topical treatment of cutaneous leishmaniasis. Previously, we showed the promising use of liposomal formulation of MA in treatment of cutaneous leishmaniasis in BALB/c mice. Here, we included Stearylamine (SA) in liposomes' structure which has antileishmanial activity by itself. . Size and encapsulation efficiency of liposomes were measured and in vitro permeation was performed using mice model. In vitro toxicity of liposomes was measured against leishmania promastigotes and amastigotes. Liposomes were used topically twice a day for 4 weeks to treat leishmania lesions in BALB\c mice model. In vitro permeation study showed liposomal formulations improved the percent of MA permeation compared with MA-cream. Promastigotes and amastigotes assay results showed significant enhanced toxicity in Liposomal-MA containing SA compared to Lip-MA. In BALB\c mice model of cutaneous leishmaniasis, liposomal groups exhibited significantly smaller lesion size compared to control groups (p < 0.01). In addition, the spleen parasite burden was significantly (P < 0.01) lower in mice treated with selected liposomal MA than in mice treated with PBS, control liposomes and MA cream. The results of this study showed that SA-liposomes encapsulated with MA might be useful as a candidate for the topical treatment of CL which merit further investigation.

Redox-responsive chitosan oligosaccharide-SS-Octadecylamine polymeric carrier for efficient anti-Hepatitis B Virus gene therapy.

DrzBC and DrzBS (10-23 DNAzyme) could block the expression of HBV e- and s- gene respectively. But the application of 10-23 DNAzyme was limited owing to the lack of appropriate delivery vehicles. Chitosan oligosaccharide-SS-Octadecylamine (CSSO), a redox-responsive nano-sized polymeric carrier, could self-aggregate and bind with DNA by electrostatic interaction at proper mass ratio. Compared with the traditional commercial carrier Lipo2000, CSSO exhibited lower cytotoxicity, efficient cellular uptake by targeting cells, and rapidly DNA released in cytoplasm after escaping from endosomes. Including the same DNA concentration, Lipo2000/(DrzBC or DrzBS) showed maximum inhibitory rate on HBeAg (47.29 ±â€¯1.86%) and HBsAg (33.58 ±â€¯0.72%) secretion after 48 h incubation, and then both decreased. In contrast, HBeAg secretion inhibition by CSSO/DrzBC and HBsAg secretion inhibition by CSSO/DrzBS were up to 73.86 ±â€¯1.77% and 67.80 ±â€¯2.51% at 48 h, and further increased to 83.83 ±â€¯2.34% and 76.79 ±â€¯2.18% at 72 h, respectively. CSSO is a promising redox-responsive polymeric carrier for efficient anti-Hepatitis B Virus gene therapy.