Photo-responsive metal-organic gels of rigid phenylene-1,3-di-substituted angular dienes with metal halides: gel-to-gel transformations triggered by [2 + 2] polymerization.

Herein, the first report on gel-to-gel transformations via [2 + 2] photopolymerization in MOGs of metal halides and rigid dienes is presented. The MOGs and their xerogels show exceptional ability to undergo [2 + 2] polymerisation upon UV irradiation. Gel-to-gel transformations are very rare as the post-modification of gelators weakens the gel and transforms it to a sol. Such transformations change the molecular assemblies into gels with altered mechanical and chemical properties. These phenomena pave the way to synthesize new MOGs with improved rigidity that cannot be synthesized otherwise.

Novel Products as Promising Therapeutic Agents for Angiogenesis Inhibition.

OBJECTIVE: Angiogenesis is the process of forming new blood vessels from pre-existing vessels and occurs during development, wound healing, and tumor growth. In this review, we aimed to present a comprehensive view of various factors contributing to angiogenesis during carcinogenesis. Anti-angiogenesis agents prevent or slow down cancer growth by interrupting the nutrients and blood supply to the tumor cells, and thus can prove beneficial for treatment. METHOD: The discovery of several novel angiogenic inhibitors has helped to reduce both morbidity and mortality from several life-threatening diseases, such as carcinomas. There is an urgent need for a new comprehensive treatment strategy combining novel anti-angiogenic agents for the control of cancer. The article contains details of various angiogenic inhibitors that have been adopted by scientists to formulate and optimize such systems in order to make them suitable for cancer. RESULTS: The results of several researches have been summarized in the article and all of the data support the claim that anti-angiogenic agent is beneficial for cancer treatment. CONCLUSION: This review focuses on novel antiangiogenic agents that play a crucial role in controlling carcinogenesis.

Nanomedicine in the Management of Alzheimer's Disease: State-of-the-Art.

Alzheimer's disease (AD) is a deadly, progressive, and irreversible brain condition that impairs cognitive abilities. Globally, it affects 32.6 million individuals, and if no viable therapies are available by 2050, that figure might rise to 139 million. The current course of treatment enhances cognitive abilities and temporarily relieves symptoms, but it does not halt or slow the disease's development. Additionally, treatments are primarily offered in conventional oral dosage forms, and conventional oral treatments lack brain specialization and cause adverse effects, resulting in poor patient compliance. A potential nanotechnology-based strategy can improve the bioavailability and specificity of the drug targeting in the brain. Furthermore, this review extensively summarizes the applications of nanomedicines for the effective delivery of drugs used in the management of AD. In addition, the clinical progress of nanomedicines in AD is also discussed, and the challenges facing the clinical development of nanomedicines are addressed in this article.

Stability issues and approaches to stabilised nanoparticles based drug delivery system.

Nanoparticles form the fundamental building blocks for many exciting applications in various scientific disciplines due to its unique features such as large surface to mass ratio, targeting potential, ability to adsorbed and carry other compound which makes them suitable for biomedical applications. However, the problem of the large-scale synthesis of nanoparticles remains challenging due to physical instability associated with nanoparticles which lead to generation of aggregates particles with high polydispersity index (PDI) indicating low particle homogeneity and eventually loss of their special nanoscale properties. The stabilisation concept can be generated by repulsive electrostatic force, which nanoparticles experience, when they are surrounded by a double layer of electric charges. Selection of proper stabiliser will govern the stability of NPs and ultimately development of optimised drug delivery system. This review summarises mechanism of physical instability issues likely to be encountered during the development of nanoformulations. It also discusses potential stabilising agents used so far and their mechanism in achieving stable nanosystems.

The rs61742690 (S783N) single nucleotide polymorphism is a suitable target for disrupting BCL11A-mediated foetal-to-adult globin switching.

BACKGROUND: B-cell lymphoma/leukaemia 11A (BCL11A) is a C2H2-type zinc-finger transcription factor protein that is a critical modulator of haemoglobin switching and suppresses the production of foetal haemoglobin. Variation in the BCL11A gene ameliorates the severity of sickle cell disease (SCD) and ß-thalassemia (ß-thal). The BCL11A gene is located on chromosome 2p16.1 and encodes an 835-amino acid protein. METHOD: Using state-of-the-art in silico tools, this study examined the most pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) that disrupt the BCL11A protein and mediate foetal-to-adult globin switching. A total of 11,463 SNPs were retrieved from the Single Nucleotide Polymorphism database (dbSNP). These included 799 in the 5' untranslated region (UTR), 486 in the 3' UTR, and 266 non-synonymous, 189 coding synonymous, six nonsense, and six stop-gained SNPs. RESULTS AND DISCUSSION: In silico tools (SIFT, SNAP, PolyPhen-2, PANTHER, I-Mutant, PROVEAN, SNPs&GO, mCSM, and PhD-SNP) predicted the five most-deleterious nsSNPs: rs61742690, rs62142605, rs17028351, rs115666026, and rs74987258. Molecular dynamic simulation and homology modelling of the mutated proteins (S783N, D643N, G451S, K670R, and M313L) of the most deleterious nsSNPs revealed their functional and structural impact. nsSNP rs61742690 was predicted to be the most deleterious, as supported by eight of the nine in silico tools. CONCLUSIONS: Complete failure in the protein-protein interactions with functional partners (KLF1 and others) and significant changes (±100% variation) in the interface energy revealed that rs61742690 (S783N) in the zinc-finger domain is a suitable target for disrupting BCL11A-mediated foetal-to-adult globin switching.

Formulation development and evaluation of nifedipine as pylorospasm inhibitor.

INTRODUCTION: In this study, different nifedipine-loaded formulations were prepared to treat pylorospasm, a sphincter muscle disorder characterized by delayed gastric emptying process. The efficacy of formulation was evaluated in patients by subjective assessment, gamma scintigraphic approaches, and confocal microscopy. METHODS: Nifedipine-loaded different formulations such as sucrose bead, pellets, and microparticles (slugging method, ionotropic gelation, and chemical denaturation) were designed. The studies were performed on 50 subjects, of which 30 subjects were treated with optimized nifedipine loaded microcapsules while 20 subjects were given capsule becosule-Z as a control. The efficacy of formulation was assessed by comparing symptoms like dyspepsia, abdominal pain, abdominal fullness, poor appetite, nausea, vomiting, and irregular motion. The effectiveness of formulation was also assessed by gamma scintigraphic studies by determining the rate of emptying of a radioactivity labeled standard meal from patients' stomach into the duodenum. Confocal microscopy was used to assess targeting potential of developed formulation. RESULTS: Drug-loaded alginate-chitosan microcapsules were found to be satisfactory, in terms of controlled drug release, surface morphology, and bioadhesive properties and thus selected for in vivo studies. Clinical studies revealed the efficacy of formulation in abolishing various GI symptoms at high altitude. Associated symptoms such as dyspepsia, abdominal pain, poor appetite, nausea, vomiting, and irregular motion were recovered by 75, 62, 76.5, 86.7, 85.7, and 37.5%, respectively in nifedipine-treated patients. In comparison, 73.7, 40, 33.3, 40, 20, and 0% recoveries were observed in patients given control treatment only. Gamma Scintigraphic studies in lab also revealed 2.425 ± 0.245 (p < .05) times improvement in gastric emptying rate in patients with diabetic gastroparesis. Confocal analysis showed better targeting and penetration in pyloric region when formulation was administered in form of high-density microcapsules. CONCLUSIONS: Results strongly suggest that nifedipine loaded mucoadhesive formulation has a targeting potential which accelerates gastric emptying process in gastroparesis patients, and thus the formulation might prove useful as a potent prokinetic agent.

Alpha ketoglutarate nanoparticles: A potentially effective treatment for cyanide poisoning.

The purpose of this research work was to prepare nanosized formulation of alpha ketoglutarate as dry powder inhaler for cyanide poisoning. Nanosizing can be approached by solid phase and liquid phase method. The different conditions encountered in both these approaches can greatly affect the particle characteristics. In this study milling and precipitation technique were compared to study their effect on α-KG particles characteristics. Differences in choice of stabilizers were observed between the two processing techniques. Sonication processes followed by HPH produced small sized particles in which Pluronic F68 was employed as stabilizing agent. Precipitation approach produced ultrafine drug particles by utilizing combination of stabilizers (PVA+PEG 400). Amongst the two sonication processes, probe sonication process produced well stabilized small sized particles. The designed particles showed 43.13±2.36% lung deposition when compared with ultrasonication and precipitation technique that showed 31.69% and 21.67% respirable fraction. The MMAD of the designed particles was found suitable for deep alveolar deposition. Clinical studies (Phase-I trial) showed whole lung deposition of 52.51% for DPI. The P/C ratio was found to be 1.02 suggesting uniform distribution of particles in different lung compartments.

Pulmonary delivery of nanosized alendronate for decorporation of inhaled heavy metals: formulation development, characterization and gamma scintigraphic evaluation.

CONTEXT: Medical management of heavy metal toxicity including radioactive ones is the cause of concern because of their increased use in energy production, healthcare and mining. As inhalation is one of the primary routes for internalization, a formulation is needed to trap metal(s) at the portal of entry itself. OBJECTIVE: Objective was to formulate and characterize a nanonized dry powder inhaler (DPI) formulation of alendronate sodium as potential inhalable antidote for chelating metal toxicants. METHODS: In vitro binding studies of alendronate with respect to seven non-radioactive heavy metals were carried out using UV-spectroscopy and HPLC. Nanonizing of alendronate particles was achieved by antisolvent precipitation using Pluronic-F68 as stabilizer. Characterization was done with the help of SEM, TEM FT-IR, XRD, DSC, NMR spectroscopy and PSD studies. In vitro and in vivo pulmonary deposition studies were carried out using gamma scintigraphy, followed by a limited pharmacokinetic study in humans. RESULTS: In vitro binding studies confirmed the chelating action of alendronate. Anderson cascade impaction showed that nano-alendronate exhibited significantly higher respirable fraction (58.25 ± 1.32%) compared to the micronized form (28.7 ± 0.59%). Scintigraphy results showed significant increase in the alveolar deposition of drug post-nanonizing. CONCLUSION: Results strongly indicate the role of nano-alendronate DPI as potential inhalable antidote for neutralizing heavy metal toxicity, including radio-metal contamination.

An approach for lacidipine loaded gastroretentive formulation prepared by different methods for gastroparesis in diabetic patients.

The present work deals with various attempts to prepare a gastroretentive formulation of lacidipine for treating gastroparesis. High density sucrose beads were modified by coating with certain polymers, but unfortunately sustained release could not be achieved. Granules were prepared by wet granulation technology using different combinations of polymers and a release of the drug was observed. The method failed to release the drug as per desired specifications. Polymeric coating followed by wet granulation was thought to be a better process to sustain the dissolution rate. The release rate can be modified by the incorporation of different polymeric coatings, but the mucoadhesive potential of granules was only 4.23% which might be due to its large size and the presence of other ingredients. Further, the lacidipine loaded microparticles were prepared by different methods such as compression, ionic gelation with TPP, ionic gelation with TPP and glutaraldehyde, spray drying and coacervation techniques. The formulations were evaluated for average particle size, surface morphology, entrapment efficiency, % yield and mucoadhesive potential. The microparticles prepared by compression method using HPMC K4M and SCMC as mucoadhesive polymers and BaSO4 as high density diluent showed poor bioadhesion (8.3%) and poor release characteristics (100% in 120 min). Ionic gelation with tripolyphosphate yielded microspheres with poor mechanical strength. In order to improve its mechanical strength, TPP ionic gelation was combined with step-wise cross-linking with glutaraldehyde. The additional solidification step to improve mechanical strength left this procedure tedious, time consuming and cytotoxic. Spray drying method gave a very low yield with 46.67% bioadhesion. The method using CaCl2 for ionotropic gelation showed the best results with regard to physical characteristics (well formed discrete, spherical surface microcapsule), particle size (88.57 ± 0.51), in vitro bioadhesion (67.33%), yield (>85%) and loading (>70%).

In vivo lung deposition and sub-acute inhalation toxicity studies of nano-sized alendronate sodium as an antidote for inhaled toxic substances in Sprague Dawley rats.

INTRODUCTION: Alendronate sodium is a bisphosphonate agent used for the treatment of osteoporosis and other bone diseases. It has a strong chelating property to bind or, to some extent, counteract the effects of substances, such as magnesium, calcium citrate, ferrous fumarate, carbonyl iron, as well as the zinc gluconate, sulfate and acetate salts. The objective of the present study was to evaluate lung deposition and sub-acute inhalation toxicity of the alendronate sodium respiratory formulation. METHODS: Particle dimension of aerosols of alendronate was measured using a particle size analyzer. Alendronate was radiolabeled using Technetium-99m for in vitro and in vivo biodistribution studies. Alendronate at doses, 0.5%, 1.0%, and 1.5% in ethanol-saline respiratory formulation was inhaled twice a day up to 5 weeks for inhalation toxicity investigations. Hematological, biochemical and lung toxicity biomarkers in bronchoalveolar lavage (BAL) fluid were determined at the end of the experiment. Histopathological analysis of lung tissues was carried out to observe any microscopic changes RESULTS: Particle size analysis revealed the size within 300-500nm. Anderson cascade impactor results showed that the particles exhibited higher respirable fraction (55.52%) with MMAD of 4.66µm. Hematology, serum biochemistry and lung toxicity biomarkers in BAL fluid performed in the sub-acute toxicity studies indicated no adverse effects of alendronate sodium inhalation except for a significant increase in cholesterol levels and marginal increase in BAL fluid protein. At autopsy, no histopathological changes in major organs were observed. CONCLUSIONS: The lung deposition and safety evaluation data observed from these studies suggested that aerosolized nanosized alendronate sodium by the inhalation route could be a new and promising route of administration as an antidote to radioactive substances through an increase in the bioavailability of the drug as well as a decrease in side effects on systemic delivery.

Nanoparticles-mediated drug delivery approaches for cancer targeting: a review.

Cancer has become the leading cause of death among different populations of the world. The treatment is limited to chemotherapy, radiation, and surgery. Selective targeting to the tumor cells is possible by nanoparticles-based drug delivery system. It maximizes the drug concentration at the desired target and protects the surrounding healthy tissues at the same time. To improve the targeting potential of the anticancer drugs, nanoparticles were optimized for the size and surface characteristics to enhance their circulation time and targeting efficiency. Passive targeting involves surface modification with polyethylene glycol to avoid its elimination by natural body defense mechanism. Active targeting involves chemical interaction with certain antigen, receptors, and genes which are over expressed during progression of disease. In addition, the article highlights recent developments in "smart"-stimulus-responsive-drug carriers designed to enhance the localization and efficacy of therapeutic payloads as compared with free drug. Enhanced targeting potential, imaging, and controlled release of drugs or therapeutic molecules could be possible through multi-functional nanocarrier. Such multi-faceted, versatile nanocarriers and drug delivery systems promise a substantial increase in the efficacy of diagnostic and therapeutic applications in pharmaceutical sciences.

Inhalation of alendronate nanoparticles as dry powder inhaler for the treatment of osteoporosis.

The precipitation technique was used to prepare non-polymeric alendronate nanoparticles. The influence of various formulation parameters on the average particle size was investigated and the effect of various stabilizers (PVA, tween, chitosan, alginate, PEG, HPMC, poloxomers) was evaluated. The selection of surfactant was a key factor to produce particles with desired properties. Poloxomer F68 was found best in achieving the minimum particle size and providing physical stability to the drug. On basis of preliminary trials, a central composite design was employed to study the effect of independent variables, drug concentration (X1), antisolvent volume (X2), stirring speed (X3), and stabilizer concentration (X4) on the average particle size. The drug and stabilizer concentrations exhibited a more significant effect on a dependent variable. The particle size varied from 62 to 803.3 nm depending upon the significant terms. The validation of optimization study, performed using six confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (±SD) as -2.32 ± 2.47. The minimum particle size (44.11 nm) was predicted at 10 mg/ml drug concentration, 20 ml antisolvent volume, 925 rpm stirring speed, and 8.5% stabilizer concentration with 98.16% experimental validity. Respirable fraction for optimized nanosized alendronate (43.85% ± 0.52%) was significantly higher when compared with commercial alendronate (17.6 ± 0.32). Mass median aerodynamic diameter of designed particles was 3.45 µm with geometric standard deviation of 2.10.

Development of nano alpha-ketoglutarate nebulization formulation and its pharmacokinetic and safety evaluation in healthy human volunteers for cyanide poisoning.

Development of nano alpha-ketoglutarate (A-KG) nebulization formulation for neutralization of inhaled cyanide ion toxicity. Objectives of the present study were to (a) develop a novel A-KG nebulization formulation against cyanide poisoning, particularly hydrogen cyanide gas (b) validate its respiratory fraction in vitro and in vivo, and (c) create its pharmacokinetic data in human volunteers. The formulation was optimized on the basis of particle size of aerosolized droplets after nebulization in 6 volunteers. Gamma scintigraphy was used to quantify total and regional lung deposition of nebulized A-KG after radiolabeling it with Technetium-99m. The formulation was optimized using 30% ethanol-saline with particle size in the range of 300-500 nm. In vitro and in vivo studies showed that drug nebulization resulted in a significant respirable fraction of 65 ± 0.6% with whole lung deposition of 13 ± 1%. Human pharmacokinetic data was derived in 6 healthy human volunteers with peak serum concentration (C(max)) of 39 ± 3 µg/ml, while the area under curve (AUC) after inhalation was 376 ± 23 µg × h/ml indicating that the drug was rapidly and completely absorbed when targeted directly to lungs. Significant lung deposition of A-KG was achieved with the developed formulation. The formulation appears to have several advantages, including the potential of neutralizing inhaled CN(-) ions in the lungs themselves. It is a safe and efficacious procedure, suitable for hospital or ambulance use in accidental cyanide poisoning cases, or as a preventive approach for fire-rescue teams.

Non-fatal work-related motor vehicle traffic crash injuries in New Zealand: analysis of a national claims database.

OBJECTIVES: This study describes event rates and associated costs from non-fatal work-related motor vehicle traffic crash (WR MVTC) injuries on public roads in New Zealand based on an analysis of the Accident Compensation Corporation (ACC) entitlement claims database. METHODS: WR MVTC injury claims between July 2004 and June 2006 were identified from the ACC Motor Vehicle Account. Cross-sectional analyses were performed to describe the characteristics of the claims. Injury rates were estimated where appropriate. RESULTS: The overall age-standardised rate of non-fatal WR MVTC injury claims during the study period was 109 per 100,000 workers per year. The majority of claimants were male (75%) and New Zealand (NZ) European (67%), and one in three of these injuries occurred among plant and machine operators and assemblers. In contrast to rates of road traffic injury resulting in deaths and hospital admissions in NZ, younger and older workers had similar proportionate representation in the claims data. The total cost associated with the 1968 claims made during the 12 months from July 2004 to June 2005 was approximately NZ$6 million, with an average cost per claim of NZ$2884. CONCLUSIONS: To our knowledge this is the first published analysis of non-fatal WR MVTC injury claims in New Zealand. These analyses identify industry and demographic groups that appear to be at increased risk of WR MVTC injuries that could be targeted for preventive interventions. However, a number of limitations in the database, including uncertainties regarding the definition and coding of crashes deemed as "work-related", under-reporting of claims, and lack of a reliable indicator of injury severity significantly compromised our ability to interpret the results. Considerable improvement in the quality and reporting of claims data is required to facilitate the utility of this information to inform injury prevention strategies.