Preparation and Characterization of Disulfiram and Beta Cyclodextrin Inclusion Complexes for Potential Application in the Treatment of SARS-CoV-2 via Nebulization.

Disulfiram (DS), known as an anti-alcoholism drug, has shown a potent antiviral activity. Still, the potential clinical application of DS is limited by its low water solubility and rapid metabolism. Cyclodextrins (CDs) have been widely used to improve the solubility of drugs in water. In this study, five concentrations of hydroxypropyl ß-cyclodextrin (HP) and sulfobutyl ether ß-cyclodextrin (SBE) were used to form inclusion complexes of DS for enhanced solubility. Solutions were freeze-dried, and the interaction between DS and CD was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). In addition, the nebulization properties of the DS-CD solutions were studied. The aqueous solubility of DS increased significantly when loaded to either of both CDs. The phase solubility of both complexes was a linear function of the CD concentration (AL type). Furthermore, physicochemical characterization studies showed a potent inclusion of the drug in the CD-DS complexes. Aerosolization studies demonstrated that these formulations are suitable for inhalation. Overall, the CD inclusion complexes have great potential for the enhancement of DS solubility. However, further studies are needed to assess the efficacy of DS-CD inclusion complexes against SARS-CoV-2 via nebulization.

Comparative Study on the Outcome of Periorbital Wrinkles Treated with Laser-Assisted Delivery of Vitamin C or Vitamin C Plus Growth Factors: A Randomized, Double-blind, Clinical Trial.

BACKGROUND: Despite promising results, laser-assisted drug delivery (LADD) is not yet considered as standard therapies and published data rely mainly on laboratory tests, animal experiments or cadaver skin. OBJECTIVES: This double-blind, prospective, randomized clinical trial investigates the impact in topical application of vitamin C and a cosmeceutical containing growth factors (GFs) on periorbital wrinkles primarily treated with laser skin resurfacing. MATERIAL AND METHODS: In total, 149 female patients with periorbital wrinkles were consented and randomized into two study groups, R-C (receiving vitamin C only) and R-CGF (receiving vitamin C and a cosmeceutical containing growth factors). The statistical analysis evaluated the efficacy of each treatment regimen using software readouts provided by a three-dimensional stereophotogrammetry system prior to treatment and three months after the procedure. Results were compared to confirm if there was a significant change in the skin roughness and the average depth of the wrinkles between the two groups after treatment. RESULTS: There was a significant reduction in both skin roughness and average depth of the wrinkles in the group treated with vitamin C and growth factors (p <0.01) than those treated with LADD followed by topical application of vitamin C alone. There were no cutaneous reactions or adverse systemic reactions observed in this study related to LADD with vitamin C and GFs. CONCLUSION: Controlled laser application might have a great potential to facilitate the absorption of exogenous macromolecules by the skin. Periorbital wrinkles were reduced in both groups, but LADD using vitamin C and GFs provided significantly better results. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Treatment of Scars with Laser-Assisted Delivery of Growth Factors and Vitamin C: A Comparative, Randomised, Double-blind, Early Clinical Trial.

BACKGROUND: Scarring can jeopardize the final result of plastic surgeries. Deep dermal injuries activate dermal fibroblasts that produce excessive amount of collagen and inflammatory cytokines and growth factors, which contributes to increased fibrous tissue and scarring tissue formation. OBJECTIVES: The aim of this early study, double-blind, prospective, randomised clinical trial was to investigate the use of laser-assisted drug delivery (LADD) for scar improvement to support the establishment of LADD as standard therapy modality and to indicate suitable drugs for dermal administration. MATERIAL AND METHODS: In total, 132 patients seeking scar treatment were consented and randomised. The control group (64 patients) received laser resurfacing immediately followed by skin surface application of Vitamin C and 68 patients received laser treatment followed by skin surface application of a cosmeceutical containing growth factors (GFs) and Vitamin C. Photographs were obtained before and three months after the procedure and submitted to three-dimensional reconstruction by the software Dermapix®. Objective measurements provided by the software were statistically analysed and established the differences in the treatment result between the two groups. RESULTS: There was a significant reduction in scar roughness and volume in both groups (p < 0.01). Mann-Whitney test confirmed that the group treated vitamin C and GFs presented significantly better results than the group treated with vitamin C alone (p < 0.01). CONCLUSION: LADD has proven efficient as scars were reduced in both study groups. Furthermore, the addition of growth factors provided statistically significant better outcomes and resulted in more inconspicuous scars. No adverse reactions were observed. CLINICAL TRIAL REGISTRATION: Plataforma Brasil under the number CAAE: 63710716.2.0000.5664. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention.

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.

Development, characterization and stability evaluation of ciprofloxacin-loaded parenteral nutrition nanoemulsions.

In this study, two licensed total parenteral nanoemulsion formulations (Clinoleic® and Intralipid®) were loaded with ciprofloxacin (CP). The physicochemical characteristics and stability profiles of the formulations were investigated using a range of drug concentrations. Furthermore, formulation stability was evaluated over a period of six months at room temperature (RT) or 4 °C. Loading CP into nanoemulsions resulted in no significant differences in their measured droplet size, polydispersity index (PI), zeta potential, and pH. Drug entrapment efficiency (EE) was relatively high for all formulations, regardless of nanoemulsion type, and the drug release was sustained over 24 h. Stability studies of all formulations were performed at 4 °C and RT for 180 and 60 days, respectively. At 4 °C for 180 days, both Clinoleic® and Intralipid® formulations at a range of drug concentrations (1-10 mg/ml) showed high stabilities measured periodically by the average droplet sizes, PI, pH, and zeta potential values. Similar results, but pH values, were shown when the formulations for both nanoemulsion stored at RT for 60 days. Overall, this study has shown that CP was successfully loaded into clinically licensed TPN lipid nanoemulsions. The resultant CP-loaded nanoemulsion formulations demonstrated desirable physicochemical properties and were stable upon storage at 4 °C for up to six months.

Ethanol-based proliposome delivery systems of paclitaxel for in vitro application against brain cancer cells.

In this study the anticancer activity of paclitaxel-loaded nano-liposomes on glioma cell lines was investigated. Soya phosphatidylcholine:cholesterol (SPC:Chol), hydrogenated soya phosphatidylcholine:cholesterol (HSPC:Chol) or dipalmitoylphosphatidylcholine:cholesterol (DPPC:Chol) in 1:1 mole ratio were used to prepare ethanol-based proliposomes. Following hydration of proliposomes, the size of resulting vesicles was subsequently reduced to nanometer scale via probe-sonication. The resulting formulations were characterized in terms of size, zeta potential and morphology of the vesicles, and entrapment efficiency of paclitaxel (PX) as well as the final pH of the preparations. DPPC-liposomes entrapped 35-92% of PX compared to 27-74% and 25-60% entrapped by liposomes made from SPC and HSPC formulations respectively, depending on drug concentration. The entrapment efficiency of liposomes was dependent on the lipid bilayer properties and ability of PX to modify surface charge of the vesicles. In vitro cytotoxicity studies revealed that PX-liposome formulations were more selective at inhibiting the malignant cells. The cytotoxicity of PX-liposomes was dependent on their drug-entrapment efficiency. This study has shown PX-liposomes generated from proliposomes have selective activity against glioma cell lines, and the synthetic DPPC phospholipid was most suitable for maximized drug entrapment and highest activity against the malignant cells in vitro.

The use of albumin solid dispersion to enhance the solubility of unionizable drugs.

In this study, solid dispersions of prednisolone (PRD) and bovine serum albumin (BSA) were prepared by spray drying and freeze drying methods using a PRD:BSA solution [20:1 molar ratio (MR)]. PRD-BSA dispersed mixtures were characterized by scanning electron microscopy (SEM), and powder X-ray diffraction (XRD), and differential scanning calorimetry (DSC). PRD-BSA physical and dispersed mixtures showed significantly higher solubility in water than that of unprocessed drug. Enhancement factor of six was obtained in both physical mixture and solid dispersion solubility studies. In-vitro dissolution and release studies under physiological conditions showed an immediate release of PRD from the solid dispersions, with almost 90% of the drug dissolved in the first 10 min. PRD was immediately released from BSA binding complex. This study demonstrates the potential for the use of BSA to enhance the solubility and dissolution rate, hence bioavailability, of the unionizable drugs.

Spray-Dried Proliposome Microparticles for High-Performance Aerosol Delivery Using a Monodose Powder Inhaler.

Proliposome formulations containing salbutamol sulphate (SS) were developed using spray drying, and the effects of carrier type (lactose monohydrate (LMH) or mannitol) and lipid to carrier ratio were evaluated. The lipid phase comprised soy phosphatidylcholine (SPC) and cholesterol (1:1), and the ratios of lipid to carrier were 1:2, 1:4, 1:6, 1:8 or 1:10 w/w. X-ray powder diffraction (XRPD) revealed an interaction between the components of the proliposome particles, and scanning electron microscopy (SEM) showed that mannitol-based proliposomes were uniformly sized and spherical, whilst LMH-based proliposomes were irregular and relatively large. Using a two-stage impinger (TSI), fine particle fraction (FPF) values of the proliposomes were higher for mannitol-based formulations, reaching 52.6%, which was attributed to the better flow properties when mannitol was used as carrier. Following hydration of proliposomes, transmission electron microscopy (TEM) demonstrated that vesicles generated from mannitol-based formulations were oligolamellar, whilst LMH-based proliposomes generated 'worm-like' structures and vesicle clusters. Vesicle size decreased upon increasing carrier to lipid ratio, and the zeta potential values were negative. Drug entrapment efficiency (EE) was higher for liposomes generated from LMH-based proliposomes, reaching 37.76% when 1:2 lipid to carrier ratio was used. The in vitro drug release profile was similar for both carriers when 1:6 lipid to carrier ratio was used. This study showed that spray drying can produce inhalable proliposome microparticles that can generate liposomes upon contact with an aqueous phase, and the FPF of proliposomes and the EE offered by liposomes were formulation-dependent.

In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates.

The present study compares the use of high generation G3 and low generation G0 Polyamidoamine (PAMAM) dendrimers as drug carriers of naproxen (NAP), a poorly water soluble drug. Naproxen was conjugated to G3 in different ratios and to G0 in a 1:1 ratio via a diethylene glycol linker. A lauroyl chain (L), a lipophilic permeability enhancer, was attached to G3 and G0 prodrugs. The G3 and G0 conjugates were more hydrophilic than naproxen as evaluated by the measurement of partitioning between 1-octanol and a phosphate buffer at pH 7.4 and pH 1.2. The unmodified surface PAMAM-NAP conjugates showed significant solubility enhancements of NAP at pH 1.2; however, with the number of NAP conjugated to G3, this was limited to 10 molecules. The lactate dehydrogenase (LDH) assay indicated that the G3 dendrimer conjugates had a concentration dependent toxicity towards Caco-2 cells. Attaching naproxen to the surface of the dendrimer increased the IC50 of the resulting prodrugs towards Caco-2 cells. The lauroyl G3 conjugates showed the highest toxicity amongst the PAMAM dendrimer conjugates investigated and were significantly more toxic than the lauroyl-G0-naproxen conjugates. The permeability of naproxen across monolayers of Caco-2 cells was significantly increased by its conjugation to either G3 or G0 PAMAM dendrimers. Lauroyl-G0 conjugates displayed considerably lower cytotoxicity than G3 conjugates and may be preferable for use as a drug carrier for low soluble drugs such as naproxen.

Liposome Delivery Systems for Inhalation: A Critical Review Highlighting Formulation Issues and Anticancer Applications.

This is a critical review on research conducted in the field of pulmonary delivery of liposomes. Issues relating to the mechanism of nebulisation and liposome composition were appraised and correlated with literature reports of liposome formulations used in clinical trials to understand the role of liposome size and composition on therapeutic outcome. A major highlight was liposome inhalation for the treatment of lung cancers. Many in vivo studies that explored the potential of liposomes as anticancer carrier systems were evaluated, including animal studies and clinical trials. Liposomes can entrap anticancer drugs and localise their action in the lung following pulmonary delivery. The safety of inhaled liposomes incorporating anticancer drugs depends on the anticancer agent used and the amount of drug delivered to the target cancer in the lung. The difficulty of efficient targeting of liposomal anticancer aerosols to the cancerous tissues within the lung may result in low doses reaching the target site. Overall, following the success of liposomes as inhalable carriers in the treatment of lung infections, it is expected that more focus from research and development will be given to designing inhalable liposome carriers for the treatment of other lung diseases, including pulmonary cancers. The successful development of anticancer liposomes for inhalation may depend on the future development of effective aerosolisation devices and better targeted liposomes to maximise the benefit of therapy and reduce the potential for local and systemic adverse effects.

A facile approach to manufacturing non-ionic surfactant nanodipsersions using proniosome technology and high-pressure homogenization.

In this study, a niosome nanodispersion was manufactured using high-pressure homogenization following the hydration of proniosomes. Using beclometasone dipropionate (BDP) as a model drug, the characteristics of the homogenized niosomes were compared with vesicles prepared via the conventional approach of probe-sonication. Particle size, zeta potential, and the drug entrapment efficiency were similar for both size reduction mechanisms. However, high-pressure homogenization was much more efficient than sonication in terms of homogenization output rate, avoidance of sample contamination, offering a greater potential for a large-scale manufacturing of noisome nanodispersions. For example, high-pressure homogenization was capable of producing small size niosomes (209 nm) using a short single-step of size reduction (6 min) as compared with the time-consuming process of sonication (237 nm in >18 min) and the BDP entrapment efficiency was 29.65% ± 4.04 and 36.4% ± 2.8. In addition, for homogenization, the output rate of the high-pressure homogenization was 10 ml/min compared with 0.83 ml/min using the sonication protocol. In conclusion, a facile, applicable, and highly efficient approach for preparing niosome nanodispersions has been established using proniosome technology and high-pressure homogenization.

Stability of parenteral nanoemulsions loaded with paclitaxel: the influence of lipid phase composition, drug concentration and storage temperature.

Paclitaxel was loaded into licensed parenteral nutrition nanoemulsions (Clinoleic® and Intralipid®) using bath sonication, and the stability of the formulations was investigated following storage for two weeks at room temperature or at 4 °C. In general, Clinoleic droplets were smaller than Intralipid droplets, being around 255 and 285 nm, respectively, for blank and freshly loaded emulsions. Regardless of storage temperature, the Clinoleic exhibited a very slight or no increase in droplet size upon storage, whilst the droplet size of the Intralipid emulsion increased significantly. The droplet size of both emulsions was minimally affected by paclitaxel concentration within the range of 0, 1, 3 and 6 mg/ml. The pH of both emulsions markedly decreased upon storage at room temperature, which was possibly attributed to the production of fatty acids resulting from phospholipid hydrolysis. However, at 4 °C, the pH of Clinoleic emulsion was unaffected by storage or paclitaxel concentration while the Intralipid emulsion demonstrated a trend for pH reduction. Both nanoemulsions had a negative zeta potential, with the Clinoleic formulations having the highest charge, possibly explaining the better size stability of this emulsion. Overall, this study has shown that paclitaxel was successfully loaded into clinically licensed parenteral emulsions and that Clinoleic showed greater stability than the Intralipid.

Efficient removal of antibiotics from water by highly crosslinked metal-alginate particles: Preparation, isotherms, kinetics, and microbiological assay.

Traces of antibiotics reaching aquatic environment lead to the emergence of antimicrobial resistance (AMR). The efficient removal of antibiotics (ATBs) traces from wastewater is essential to tackle the AMR. In this study, a novel solid-state crosslinking method of alginate (ALG) was developed and applied to specifically remove ATBs from water. A wide range of crosslinkers (Ca2+, Zn2+, Cu2+, Ni2+, Fe3+ and Al3+) was used and the crosslinking nature, density, and distribution were evidenced by FTIR, ICP-MS, and SEM-EDS. Compared with ionotropic gelation, the novel solid-state crosslinking method proved superior in term of ease of production, high crosslinking degree, and ATBs removal capacity. Fe-ALG and Zn-ALG showed high removal capacity of ciprofloxacin (356.5 mg/g and 928.6 mg/g) and doxycycline (90 mg/g and 690 mg/g), however, they were less effective toward amoxicillin (11.5 mg/g and 6 mg/g). Removal isotherms and kinetics followed type I and pseudo-second order suggesting a chemisorption removal mechanism. Fe-ALG was successfully regenerated with no loss in ATB removal capacity. The microbiological assay showed significant reductions of antibacterial activities after ATBs removal from water. Overall, metal-ALG systems obtained by solid-state crosslinking are promising for ATBs removal from wastewater giving the ease of production, high efficiency, regenerability, and scalability potential.

Preparation and Characterisation of Zinc Diethyldithiocarbamate-Cyclodextrin Inclusion Complexes for Potential Lung Cancer Treatment.

Zinc diethyldithiocarbamate (Zn (DDC)2), a disulfiram metabolite (anti-alcoholism drug), has shown a strong anti-cancer activity in vitro. However, its application was limited by its low aqueous solubility and rapid metabolism. In this study, the solubility enhancement of Zn (DDC)2 is investigated by forming inclusion complexes with cyclodextrins. The inclusion complexes were prepared using two different types of beta-cyclodextrins, SBE-CD and HP-CD. Phase solubility diagrams for the resulting solutions were assessed; subsequently, the solutions were freeze-dried for further characterisation studies using DSC, TGA, XRD, and FTIR. The cytotoxic activity of the produced inclusion complexes was evaluated on human lung carcinoma cells using the MTT assay. The solubility of Zn (DDC)2 increased significantly upon adding beta-cyclodextrins, reaching approximately 4 mg/mL for 20% w/w CD solutions. The phase solubility diagram of Zn (DDC)2 was of the Ap-type according to the Higuchi and Connors model. Characterisation studies confirmed the inclusion of the amorphous drug in the CD-Zn (DDC)2 complexes. The cytotoxicity of Zn (DDC)2 was enhanced 10-fold by the inclusion complexes compared to the free drug. Overall, the resulting CD-Zn (DDC)2 inclusion complexes have a potential for treatment against lung cancer.

PLGA-Nano-Encapsulated Disulfiram Inhibits Hypoxia-Induced NF-κB, Cancer Stem Cells, and Targets Glioblastoma In Vitro and In Vivo.

Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NF-κB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram, an antialcoholism drug, has very strong NF-κB-inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of disulfiram and in vivo anti-GBM efficacy of poly lactic-co-glycolic acid nanoparticle-encapsulated disulfiram (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs and also examined the anti-GSC activity of disulfiram in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NF-κB, hypoxia-inducible factor-1α (HIF1α), and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characteristics of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NF-κB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NF-κB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSCs, and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines.

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells.

Scientific validation of three-dimensional stereophotogrammetry compared to the IGAIS clinical scale for assessing wrinkles and scars after laser treatment.

Measuring outcomes from treatments to the skin is either reliant upon patient's subjective feedback or scale-based peer assessments. Three-Dimensional stereophotogrammetry intend to accurately quantify skin microtopography before and after treatments. The objective of this study is comparing the accuracy of stereophotogrammetry with a scale-based peer evaluation in assessing topographical changes to skin surface following laser treatment. A 3D stereophotogrammetry system photographed skin surface of 48 patients with facial wrinkles or scars before and three months after laser resurfacing, followed immediately by topical application of vitamin C. The software measured changes in skin roughness, wrinkle depth and scar volume. Images were presented to three observers, each independently scoring cutaneous improvement according to Investigator Global Aesthetic Improvement Scale (IGAIS). As for the results, a trend reflecting skin/scar improvement was reported by 3D SPM measurements and raters. The percentage of topographical change given by the raters matched 3D SPM findings. Agreement was highest when observers analysed 3D images. However, observers overestimated skin improvement in a nontreatment control whilst 3D SPM was precise in detecting absence of intervention. This study confirmed a direct correlation between the IGAIS clinical scale and 3D SPM and confirmed the efficacy and accuracy of the latter when assessing cutaneous microtopography alterations as a response to laser treatment.

Drink types unmask the health risks associated with alcohol intake - Prospective evidence from the general population.

BACKGROUND & AIMS: Uncertainty still exists on the impact of low to moderate consumption of different drink types on population health. We therefore investigated the associations of different drink types in the form of beer/cider, champagne/white wine, red wine and spirits with various health outcomes. METHODS: Over 500,000 participants were recruited to the UK Biobank cohort. Alcohol consumption was self-reported as pints beer/cider, glasses champagne/white wine, glasses of red wine, and measures of spirits per week. We followed health outcomes for a median of 7.02 years and reported all-cause mortality, cardiovascular events, ischemic heart disease, cerebrovascular events, and cancer. RESULTS: In continuous analysis after excluding non-drinkers, beer/cider and spirits intake associated with an increased risk for all-cause mortality (beer/cider: hazard ratio, 1.56; 95% confidence interval, 1.45-1.68; spirits: 1.47; 1.35-1.60), cardiovascular events (beer/cider: 1.25; 1.17-1.33; spirits: 1.25; 1.16-1.36), ischemic heart disease (beer/cider:1.12; 0.99-1.26 [P = 0.056]; spirits: 1.17; 1.02-1.35), cerebrovascular disease (beer/cider: 1.63; 1.32-2.02; spirits: 1.59; 1.25-2.02) and cancer (beer/cider: 1.14; 1.05-1.24; spirits: 1.14; 1.03-1.26), while both champagne/white wine and red wine associated with a decreased risk for ischemic heart disease only (champagne/white wine: 0.84; 0.72-0.98; red wine: 0.88; 0.77-0.99). CONCLUSIONS: Our findings do not support the notion that alcohol from any drink type is beneficial to health. Consuming low levels of beer/cider and spirits already associated with an increased risk for all health outcomes, while wine showed opposite protective relationships only with ischemic heart disease.

Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment.

Disulfiram (DS), an anti-alcoholism medicine, shows strong anti-cancer activity in the laboratory, but the application in clinics for anti-cancer therapy has been limited by its prompt metabolism. Conventional liposomes have shown limited ability to protect DS. Therefore, the aim of this study is to develop PEGylated liposomes of DS for enhanced bio-stability and prolonged circulation. PEGylated liposomes were prepared using ethanol-based proliposome methods. Various ratios of phospholipids, namely: hydrogenated soya phosphatidylcholine (HSPC) or dipalmitoyl phosphatidylcholine (DPPC) and N-(Carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2000) with cholesterol were used. DS was dissolved in the alcoholic solution in different lipid mol% ratios. The size of the resulting multilamellar liposomes was reduced by high-pressure homogenization. Liposomal formulations were characterized by size analysis, zeta potential, drug loading efficiency and stability in horse serum. Small unilamellar vesicles (SUVs; nanoliposomes) were generated with a size of approximately 80 to 120 nm with a polydispersity index (PDI) in the range of 0.1 to 0.3. Zeta potential values of all vesicles were negative, and the negative surface charge intensity tended to increase by PEGylation. PEGylated liposomes had a smaller size (80-90 nm) and a significantly lower PDI. All liposomes showed similar loading efficiencies regardless of lipid type (HSPC or DPPC) or PEGylations. PEGylated liposomes provided the highest drug biostability amongst all formulations in horse serum. PEGylated DPPC liposomes had t1/2 =77.3 ± 9.6 min compared to 9.7 ± 2.3 min for free DS. In vitro cytotoxicity on wild type and resistant colorectal cancer cell lines was evaluated by MTT assay. All liposomal formulations of DS were cytotoxic to both the wild type and resistant colorectal cancer cell lines and were able to reverse chemoresistance at low nanomolar concentrations. In conclusion, PEGylated liposomes have a greater potential to be used as an anticancer carrier for disulfiram.

Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery.

Dendrimers constitute a class of polymers that possess a well-defined structure allowing the precise control of size, shape and terminal group functionality. Their utility has been explored for a wide range of pharmaceutical applications. There is growing interest in the design and synthesis of novel biocompatible dendrimers and a number of novel dendrimer architectures are discussed in this review. Recently, there has also been interest in the design of drug-dendrimer prodrugs and several of these systems are described, with emphasis on how the properties of such carriers may be tailored via surface engineering.