Polysaccharide and monosaccharide guided liver delivery of Sorafenib Tosylate - A nano-strategic approach and comparative assessment of hepatospecificity.

Hepatospecific delivery by ligand based receptor targeting is an established strategy to augment therapy associated with liver diseases and disorders. Previously, we have investigated the effect of ligand headgroup on cellular uptake mediated by the asialoglycoprotein receptor by in silico and in vitro approach. In this paper, we report the design of agarose based liposomes for delivery to liver cancer cells and provide a proof of concept of the targeting efficiency against galactose liposomes using an in vivo approach. Sorafenib Tosylate loaded targeting liposomes were developed and optimized using factorial design. Comparative evaluation including cell cytotoxicity, pharmacokinetics and biodistribution and hepatospecific uptake was performed for both the liposomal systems. The formulations possessed a particle size of 150 - 180 nm and a zeta potential of 30 - 60 mV depending on the amount of ligand and drug loading, with more than 90% entrapment efficiency. A two-fold increase in cytotoxicity was observed with agarose-based liposomes as compared to galactose based liposomes. In vivo PK evaluation indicated a reduction in half life of drug when loaded in agarose ligand loaded system, probably due to greater uptake in the liver as evidenced in biodistribution study. Intrahepatic disposition revealed a higher PC/NPC uptake ratio with the targeted systems as compared to conventional liposomes, although the agarose-based system resulted in highest uptake ratio. A biocompatible platform for specific delivery of drugs to hepatocytes was established validating a rational approach to design liver targeting systems.

Smartphones and tooth brushing: content analysis of the current available mobile health apps for motivation and training.

INTRODUCTION: Smartphone mobile app is an innovative concept for health behaviour-based interventions. AIM: The present study aimed to analyse apps developed for smartphones that promote tooth brushing amongst children using the Coventry, Aberdeen, and London-Refined (CALO-RE) taxonomy for behaviour change. MATERIALS AND METHODS: Tooth brushing apps available in English and free to download that purported to assist with brushing were searched on the Apple app store using search terms based on Boolean logic and included AND combinations for keywords tooth brushing, children, toothbrush and motivation in the health and fitness category; six apps met the inclusion criteria and were downloaded. The behaviour change taxonomies were assessed individually for each app and scored as per coding and analysed for presence or absence. RESULTS: Only three of the behaviour change taxonomies were present in all apps, i.e. information provision (general), goal setting (behaviour) and prompt practice. Setting graded tasks, self-monitoring of behavioural outcome, demonstration of behaviour, prompt use of imagery and time management were included in four out of six apps. CONCLUSION: The present study explores a new arena for oral healthcare motivation and prevention in children through the use of mobile phone apps.

Dataset on statistical reduction of COD by electrocoagulation process using RSM.

Viable and low treatment cost is a challenge for municipal wastewater, therefore, an efficient and cost effective electrocoagulation (EC) process was studied to treat domestic sewage (DS) in laboratory batch process using SS-304 as electrode material. Effects of various parameters like pH, current density (CD), electrode configuration in numbers and treatment time (tR) were tested to find optimum operating condition for COD and other pollutants removal. The experiments were also planned to optimize the operating parameters through response surface methodology (RSM) based central composite design (CCD) which gave 77.78% COD reduction at CD = 27.78 A/m2 and tR = 20 min respectively.

Oral administration of 3,3'-diselenodipropionic acid prevents thoracic radiation induced pneumonitis in mice by suppressing NF-kB/IL-17/G-CSF/neutrophil axis.

The incidence of symptomatic radiation induced lung pneumonitis (RILP), a major dose limiting side effect of thoracic radiotherapy, is in the range of 15-40%. Therapeutic options for the prevention and treatment of RILP are limited. Hence there is a need for developing novel radioprotectors to prevent RILP which can be patient compliant. This study sought to evaluate the efficacy of oral 3,3'-diselenodipropionic acid (DSePA), a novel selenocystine derivative to prevent RILP. C3H/HeJ (pneumonitis responding) mice received a single dose of 18 Gy, whole thorax irradiation and a subset were treated with DSePA orally (2.5 mg/kg), three times per week beginning 2 h post irradiation and continued till 6 months. DSePA delayed onset of grade ≥ 2 RILP by 45 days compared to radiation control (~105 versus ~60 days). It also reversed the severity of pneumonitis in 3/10 radiation treated mice leading to significant improvement in asymptomatic survival compared to radiation control (~180 versus ~102 days). DSePA significantly (p < 0.05) reduced the radiation-mediated infiltration of polymorphonuclear neutrophils (PMN) and elevation in levels of cytokines such as IL1-ß, ICAM-1, E-selectin, IL-17 and TGF-ß in the bronchoalveolar lavage fluid. Moreover DSePA lowered PMN-induced oxidants, maintained glutathione peroxidase activity and suppressed NF-kB/IL-17/G-CSF/neutrophil axis in the lung of irradiated mice. Additionally, this compound did not protect A549 (lung cancer) derived xenograft tumor from radiation exposure in SCID mice. DSePA offers protection to normal lung against RILP without affecting radiation sensitivity of tumors. It has the potential to be developed as an oral agent for preventing RILP.

Drug-sensitive FGFR3 mutations in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.

Comparison of alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction, no hypoglycaemia and no weight gain in type 2 diabetes mellitus.

This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.

Six-year analysis of compliance to weekly concurrent chemoradiotherapy in head and neck carcinomas.

OBJECTIVES: To evaluate treatment compliance to weekly concurrent chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective analysis. SETTING: Tertiary care hospital. MAIN OUTCOME MEASURES: Overall treatment time (OTT), acute radiation morbidity and treatment completion rate without prolongation of overall treatment time of more than 2 days. RESULTS: Three hundred and seventy-eight head and neck carcinoma patients treated with radical CRT with 70 Gy/35 fractions of radiotherapy with weekly cisplatin 40 mg/m(2) were included in the study. Median age was 52 years (range 22-77 years), oropharynx was most commonly (54%) involved site, and 55% were in stage IV disease. Majority (86%) of patients were able to complete cancer-directed therapy, median OTT was 52 days (46-140 days). Nineteen per cent of patients completed treatment without prolongation of OTT beyond 2 days and 68% of patients there completed treatment prolongation of OTT beyond 7 days. Nearly, sixty-six of the patients experienced grade II or higher acute radiation morbidities. CONCLUSIONS: Delivery of weekly low-dose concurrent CRT is safe and feasible. Two-thirds of the patients experienced treatment prolongation of more than 2 days and 14% could not complete treatment. Results within in the study suggest to a greater need to lay emphasis on continuity of a course of radical CRT for HNSCC.

MACROBID INDUCED HEPATITIS.

More than 900 drugs, toxins and herbs have been reported to cause liver injury. Drugs account for 20-40 percent of all instances of fulminant hepatic failure.

Freeze-dried amorphous dispersions for solubility enhancement of thermosensitive API having low molecular lipophilicity.

The present study focuses on the development of an alternative 'thermally gentle' strategy such as freeze-drying to obtain not only solubility enhanced but also physically stabilised amorphous solid dispersions of acetazolamide, which melt with decomposition (M.P.~260°C). The solid dispersions were prepared by freeze-drying an aqueous dispersion of acetazolamide containing a lyoprotectant as sugar alcohol (mannitol) in 1:0.5, 1:1 and 1:2 proportions by weight. All the proportions of solid dispersions reported a marked increase in solubility characteristics compared to those of pure drug; with outstanding performance by 1:1 ratio of about 6 folds rise in saturation solubility and 90% drug release in about initial 30 minutes. This could be attributed to the formation amorphous molecular dispersions, cosolvent effect of mannitol on dispersed acetazolamide as well as its local solubilisation effect at the diffusion layer. During stability study also, 1:1 ratio of solid dispersions reported an insignificant change in solubility characteristics subjected to an unchanged amorphous nature. Such physical stability could be attributed to decreased molecular mobility of the drug molecules in amorphous carrier because of weaker drug-carrier interactions. Thus, it was demonstrated that freeze-drying is an effective method of forming dissolution-enhanced, amorphous solid dispersions of thermally degradable APIs.

Production of high titre antibody response against Russell's viper venom in mice immunized with ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine.

Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. The aim of the study was to assess the production of antibody response against Russell's viper venom in mice after prophylactic immunization with ethanolic extract of fruits of Piper longum L. and piperine. The mice sera were tested for the presence of antibodies against Russell's viper venom by in vitro lethality neutralization assay and in vivo lethality neutralization assay. Polyvalent anti-snake venom serum (antivenom) manufactured by Haffkine Bio-Pharmaceutical Corporation Ltd. was used as standard. Further confirmation of presence of antibodies against the venom in sera of mice immunized with PLE and piperine was done using indirect enzyme-linked immunosorbent assay (ELISA) and double immunodiffusion test. Treatment with PLE-treated mice serum and piperine-treated mice serum was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay. ELISA testing indicated that there were significantly high (p<0.01) levels of cross reactions between the PLE and piperine treated mice serum and the venom antigens. In double immunodiffusion test, a white band was observed between the two wells of antigen and antibodies for both the PLE-treated and piperine-treated mice serum. Thus it can be concluded that immunization with ethanolic extract of fruits of Piper longum and piperine produced a high titre antibody response against Russell's viper venom in mice. The antibodies against PLE and piperine could be useful in antivenom therapy of Russell's viper bites. PLE and piperine may also have a potential interest in view of the development of antivenom formulations used as antidote against snake bites.

Treatment of wastewater by electrocoagulation: a review.

The electrocoagulation (EC) process is an electrochemical means of introducing coagulants and removing suspended solids, colloidal material, and metals, as well as other dissolved solids from water and wastewaters. The EC process has been successfully employed in removing pollutants, pesticides, and radionuclides. This process also removes harmful microorganisms. More often during EC operation, direct current is applied and electrode plates are sacrificed (dissolved into solution). The dissolution causes an increased metal concentration in the solution that finally precipitates as oxide precipitates. Due to improved process design and material of construction, the EC process is being widely accepted over other physicochemical processes. Presently, this process has gained attention due to its ability to treat large volume and for its low cost. The aim of this study is to review the mechanism, affecting factors, process, and application of the electrocoagulation process.

Antidiabetic and antihyperlipidemic effects of Thespesia populnea fruit pulp extracts on alloxan-induced diabetic rats.

Present study was carried to find out the antihyperglycemic and antihyperlipidemic activity of ethanol and aqueous extract of Thespesia populnea fruit pulp on alloxan-induced diabetic rats. Diabetes was induced in rats by administration of alloxan (150 mg/kg, i.p.). After the successful induction of experimental diabetes, the rats were divided into five groups each comprising a minimum of six rats. Phytochemical analysis and acute toxicity study of extracts was also done. The effects of extracts and metformin on fasting blood glucose and plasma lipid were examined for 28 days. Statistical analysis was carried out by using analysis of variance followed by Dunnet's multiple comparison test and paired t-test were done as the test of significance using GraphPad Prism. P≤0.05 was considered as the minimal level of statistical significance. Therapeutic dose of extract was found to be 200 mg/kg on the basis of acute toxicity study. Aqueous and alcoholic extract showed a significant reduction in blood glucose levels as well as a lipid profile of diabetic rats at the end of 28(th) day of treatment. However, in groups treated with plant extract the reduction in the blood glucose and improvement in lipid profile was slightly less than that achieved with the standard group (metformin). From this study, it can be concluded that ethanol and aqueous extract of Thespesia populnea exhibited significant antihyperglycemic and antihyperlipidemic effects on alloxan-induced diabetic rats.

Anti-snake venom activities of ethanolic extract of fruits of Piper longum L. (Piperaceae) against Russell's viper venom: characterization of piperine as active principle.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. AIM OF THE STUDY: To examine the ability of ethanolic extract of fruits of Piper longum L., Piperaceae (PLE) and piperine, one of the main active principles of Piper longum, to inhibit the Russell's viper (Doboia russelii, Viperidae) snake venom activities. MATERIALS AND METHODS: Anti-snake venom activities of ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine against Russell's viper venom was studied in embryonated fertile chicken eggs, mice and rats by using various models as follows: inhibition of venom lethal action, inhibition of venom haemorrhagic action (in vitro), inhibition of venom haemorrhagic action (in vivo), inhibition of venom necrotizing action, inhibition of venom defibrinogenating action, inhibition of venom induced paw edema, inhibition of venom induced mast cell degranulation, creatine kinase assay and assay for catalase activity. RESULTS: PLE was found to inhibit the venom induced haemorrhage in embryonated fertile chicken eggs. Administration of PLE and piperine significantly (p<0.01) inhibited venom induced lethality, haemorrhage, necrosis, defibrinogenation and inflammatory paw edema in mice in a dose dependent manner. PLE and piperine also significantly (p<0.01) reduced venom induced mast cell degranulation in rats. Venom induced decrease in catalase enzyme levels in mice kidney tissue and increase in creatine kinase enzyme levels in mice serum were significantly (p<0.01) reversed by administration of both PLE and piperine. CONCLUSIONS: PLE possesses good anti-snake venom properties and piperine is one of the compounds responsible for the effective venom neutralizing ability of the plant.

Drug resinates an attractive approach of solubility enhancement of atorvastatin calcium.

A substantial number of new chemical entities and marketed drugs show poor solubility characteristics and amorphisation is one of the favorable approaches to enhance solubility characteristics of such poorly soluble drugs. Formulation efforts in the present study were devoted to investigate amorphisation of a model poorly soluble drug, atorvastatin calcium by molecular complexation with anion exchange resin, Duolite(®)AP 143/1093 and hence enhancement in its solubility characteristics. Drug resinates in 1:1, 1:2, and 1:4 weight ratios were prepared by simple batch operation and subsequently studied for drug content, residual solvent content, molecular interactions, solid state characterisation and solubility characteristics. During initial characterisation, all the proportions of drug resinates, except 1:1 proportion showed partial amorphisation of the drug, whereas 1:1 proportion showed complete amorphisation of the drug. This proportion reported distinctly enhanced solubility characteristics over pure drug and other proportions. Such amorphisation and solubility enhancement could be attributed to the binding of individual drug molecules to the functional sites of the resin molecules, either partially or completely, resulting in reduction of crystal lattice energy, a main barrier to dissolution. Hydrophilic nature of ion exchange resin matrices also assisted in enhancing dissolution of the drug from the resinates. During accelerated stability study, there was an insignificant decrease in solubility characteristics of the drug and its amorphous form was also found to be stable in 1:1 proportion. Atorvastatin resinates formed in 1:1 weight ratio were in stoichiometric proportion and such drug resinates in stoichiometric proportion showed to have tremendous potential in conversion of crystalline form of drug substances to its amorphous form and subsequent stabilisation. It hence proved to be a very effective, yet simple approach for improving solubility characteristics of poorly soluble actives.

Cellular interactions and stimulated biological functions mediated by nanostructured carbon for tissue reconstruction and tracheal tubes and sutures.

Nylon 6,6 is used for biological applications including gastrointestinal segments, tracheal tubes and sutures, vascular graft, and for hard tissue reconstruction. While it is a relatively inexpensive polymer, it is not widely acceptable as a preferred biomaterial because of bioactivity. To this end, we have discovered the exciting evidence that introduction of a novel nanostructured carbon, graphene, in the void space between the nylon chains and processing at elevated pressure favorably stimulates cellular functions and provides high degree of cytocompatibility. The cell-substrate interactions on stand alone Nylon 6,6 and Nylon 6,6-graphene oxide hybrid system were investigated in terms of cell attachment, viability, proliferation, and assessment of proteins, actin, vinculin, and fibronectin. The enhanced biological functions in the nanostructured hybrid system are attributed to relatively superior hydrophilicity of the surface and to the presence of graphene. Furthermore, it is proposed that the negatively charged graphene interacts with the polar nature of cells and the culture medium, such that the interaction is promoted through polar forces. This is accomplished by investigating cell attachment, proliferation, and morphology, including cytomorphometry evaluation, and quantitative assessment of prominent proteins, actin, vinculin, and fibronectin that are sensitive to cell-substrate interactions. Osteoblasts were studied to establish the practical viability of the hybrid nanostructured biomaterial. The study strengthens the foundation for utilizing nano- or quantum-size effects of nanostructured biomaterials.

Osteoblasts response to nylon 6,6 blended with single-walled carbon nanohorn.

Bioactivity is an important aspect that can be appropriately used to tune the cellular interactions occurring at the biomaterial-physiological interface. In this regard, we explore here the nano- or quantum-size effects of a highly dispersible nanostructured carbon present in the void space between the polymers chains (Nylon 6,6) in modulating the cellular functions when osteoblasts are seeded on biocompatible substrates. The filling-up of void space in polymer facilitates filopodia to access the extracellular matrix, enabling integrin receptors to bind to the artificial biomedical device, promoting cellular interactions. In this regard, the fundamental principles of materials processing and cellular biology were combined to elucidate the mechanism of cell-substrate interactions and the molecular machinery controlling the cell response. This is accomplished by investigating cell attachment, proliferation, and morphology, including cytomorphometry evaluation and quantitative assessment of prominent proteins, actin, vinculin, and fibronectin that are sensitive to cell-substrate interactions.

Effect of biologically synthesised silver nanoparticles on Staphylococcus aureus biofilm quenching and prevention of biofilm formation.

The development of green experimental processes for the synthesis of nanoparticles is a need in the field of nanotechnology. In the present study, the authors reported rapid synthesis of silver nanoparticles using fresh leaves extract of Cymbopogan citratus (lemongrass) with increased stability. The synthesised silver nanoparticles were found to be stable for several months. UV-visible spectrophotometric analysis was carried out to assess the synthesis of silver nanoparticles. The synthesised silver nanoparticles were further characterised by using nanoparticle tracking analyser (NTA), transmission electron microscope (TEM) and energy-dispersive x-ray spectra (EDX). The NTA results showed that the mean size was found to be 32 nm. Silver nanoparticles with controlled size and shape were observed under TEM micrograph. The EDX of the nanoparticles confirmed the presence of elemental silver. These silver nanoparticles showed enhanced quorum quenching activity against Staphylococcus aureus biofilm and prevention of biofilm formation which can be seen under inverted microscope (40X). In the near future, silver nanoparticles synthesised using green methods may be used in the treatment of infections caused by a highly antibiotic resistant biofilm.

Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate.

Zolpidem tartarate is a non-benzodiazepine, sedative-hypnotic, which finds its major use in various types of insomnia. The present work relates to development of multiparticulate floating drug delivery system based on gas generation technique to prolong the gastric residence time and to increase the overall bioavailability. Modified release dosage form of zolpidem tartarate adapted to release over a predetermined time period, according to biphasic profile of dissolution, where the first phase is immediate release phase for inducing the sleep and the second phase is modified release phase for maintaining the sleep up to 10 h. The system consists of zolpidem tartarate layered pellets coated with effervescent layer and polymeric membrane. The floating ability and in vitro drug release of the system were dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the drug layered pellets, and coating level of the polymeric membrane (Eudragit(®) NE 30D). The system could float completely within 5 min and maintain the floating over a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate with rapid floating and modified drug release was obtained.

Toxicity assessment of free form of heavy metals in aqueous media on earthworm Eudrillus eugeniae.

Metals are found in free and also in combined forms. In order to get information on the effect of free forms of heavy metals on earthworms the aqueous extracts of metals were tested on earthworms both in individual form and also in combined form. Different concentrations, i.e. 1 ppm, 5 ppm, and 10 ppm, were selected arbitrarily and were used in the experiments. Metals like copper, cadmium, chromium, zinc and lead were used. Earthworms' Eudrillus eugeniae activity, i.e. their response to the toxicity of metals, was monitored continuously for 5 h. It can be concluded that free form/ionic form/dissolved form of heavy metals are more toxic for earthworms, concurrent with findings of workers who have drawn same inference during studies on aquatic organisms. Earthworms can serve as biomarkers for wastewater and sludge treatment studies as they have shown typical adverse body reactions and symptoms altogether different in reaction to each of the metals during aqueous medium studies. It can be inferred that, if earthworms are utilised for treating wastewater and sludges containing these five heavy metals, one can ascertain the presence of individual metal concentrations in the wastewaters and sludges by studying the typical body reactions of earthworms during the treatment.