The Potential Efficacy of R8-Modified Paclitaxel-Loaded Liposomes on Pulmonary Arterial Hypertension

Purpose

In this paper, a novel liposomal formulation of paclitaxel modified with octaarginine (R8) was fabricated and the therapeutic efficacy of it on pulmonary arterial hypertension was evaluated.

Methods

Octaarginine-modified stealth liposomes loaded with PTX (R8-PTX-LIP) were prepared and characterized. Vector cytoxicity and anti-proliferation ability of different formulations on primary cultured VSMCs were determined with MTT assay. The uptake capacity of VSMCs on different formulations were evaluated by flow cytometry, and the influences on cytoskeletons of liposomes were investigated by cytoskeleton staining with rhodamine-phalloidin. The biodistribution of liposomes were imaged by a CCD camera using a near-infrared fluorophore DiD. The therapeutic efficacy of different PTX-formulations of PAH was evaluated by hemodynamic measurement, right ventricular hypertrophic parameters and vessel diameters.

Results

The cellular uptake of R8 modified liposomes (R8-LIP) was improved noticeably compared with other groups. All liposomes did not exert cytotoxicity on VSMCs in 24 h. R8-PTX-LIP exhibited the strongest inhibitory effect on the proliferation of VSMCs among all the formulations (p?<?0.001). R8-PTX-LIP could reverse the phenotype transformation, and inhibit cell migration. mPAP, (RV/LV+S) and the wall thickness of small distal pulmonary arteries of rats treated with R8-PTX-LIP were significantly lower than those from other groups (p?<?0.001).

Conclusions

In conclusion, the drug delivery system of R8-modified paclitaxel-loaded liposomes we established showed pronounced inhibitory effect over VSMCs proliferation and cytoskeleton formation in vitro, a stronger pulmonary delivery ability in vivo, and was effective on PAH, showing the potential for pulmonary drug delivery system for PAH treatment.     

Sensory reinforcement as a predictor of cocaine and water self-administration in rats

Rationale

The ability of locomotor activity in a novel environment (Loco) and visual stimulus reinforcement (VSR) to predict acquisition of responding for cocaine and water reinforcers in the absence of explicit audiovisual signals was evaluated.

Methods

In Experiment 1 (Exp 1), rats (n?=?60) were tested for VSR, followed by Loco, and finally acquisition of responding for cocaine (0.3 mg/kg/inf). In Experiment 2 (Exp 2), rats (n?=?32) were tested for VSR, followed by Loco, and finally acquisition of responding for water (0.01 mL/reinforcer).

Results

There were three main findings. First, Loco and VSR were significantly associated (Exp 1: r?=?0.49, p?<?0.00; Exp 2: r?=?0.35, p?<?0.05). Second, neither Loco (r?=?.00, p?=?0.998) nor VSR (r?=??0.12, p?=?0.352) predicted acquisition of cocaine SA. Third, in the subgroup of animals that acquired cocaine SA, VSR (r?=?0.41, p?<?0.01) but not Loco (r?=?0.28, p?=?0.10) was positively associated with operant responding for cocaine. Both Loco and VSR (Loco: r?=?0.37, p?<?0.04; VSR: r?=?0.51, p?<?0.00) were positively associated with operant responding for water reinforcers.

Conclusions

The results indicate that VSR is at least as good a predictor of cocaine reinforced responding as Loco. VSR was predictive of operant responding for both drug and water reinforcers, while Loco was found to be predictive of responding only for water reinforcers. In studies that present visual stimuli in association with drug delivery, Loco may be predicting acquisition of responding for VSR rather than drug.     

Biodistribution,Tumor Uptake and Efficacy of 5-FU-Loaded Liposomes: Why Size Matters

Purpose

We have investigated the impact of particle size on the biodistribution, tumor uptake and antiproliferative efficacy of 5-FU-loaded liposomes.

Methods

Three different batches of pegylated liposomes varying in size (i.e., 70, 120 and 250 nm respectively) were tested. The active compounds encapsulated were an equimolar mix of 5-FU, 2′-deoxyinosine and folinic acid. Liposomes were subsequently tested on the human breast cancer model MDA231 cells, a model previously found to be resistant to 5-FU. In vitro, antiproliferative efficacy and microscopy studies of liposomes uptake were carried out. In vivo, comparative biodistribution and efficacy studies were performed in tumor-bearing mice.

Results

Difference in size did not change in vitro antiproliferative activity. Fluorescence-Microscopy studies showed that liposomes were mainly uptaken by tumor cells through a direct internalization process, regardless of their size. Biodistribution profiles in tumor-bearing mice revealed higher accumulation of small liposomes in tumors throughout time as compared with normal and large liposomes (p?in vivo efficacy studies showed at study conclusion that a 68% reduction in tumor size was achieved with small liposomes (p?Conclusion This study suggests that particle size is critical to achieve higher selectivity and efficacy in experimental oncology, including in resistant tumors.     

Multi-functional Liposomes Enhancing Target and Antibacterial Immunity for Antimicrobial and Anti-Biofilm Against Methicillin-Resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>

Purpose

The aim of this study was to prepare wheat germ agglutinin (WGA)-modified liposomes encapsulating clarithromycin and to evaluate their in vitro and in vivo efficacy against Methicillin-resistant Staphylococcus aureus (MRSA).

Methods

Physicochemical parameters, minimum inhibitory concentrations, in vitro killing kinetic, cellular uptake, biofilm formation inhibition and pre-formed biofilm destruction, biodistribution, in vivo antibacterial efficacy against MRSA, and phagocytosis into macrophages for liposomes loading clarithromycin were determined.

Results

The minimum inhibitory concentration and the time–kill curve for WGA-modified liposomal clarithromycin were better than those of free and nonmodified liposomal clarithromycin. Flow cytometry analysis displayed that liposomes could deliver more Coumarin 6, a fluorescent probe, into bacteria because of the conjugation of WGA. Besides, WGA-modified liposomal clarithromycin inhibited formation of S. aureus (ATCC 29213) and MRSA biofiom, and prompted the biofilm disassembly at lower concentrations below MIC. Effective accumulation of liposomes was displayed in the enterocoelia of the mice because of WGA. The number of MRSA colony-forming units in the kidney and spleen in mice treated with WGA-modified liposomal clarithromycin was significantly lower than that treated with free and nonmodified clarithromycin (p?<?0.05). Intracellular localization of MRSA occurred in a significantly higher proportion of macrophage exposed to WGA-modified liposomes compared to those exposed to nonmodified liposomes.

Conclusions

Liposome modified by WGA is a promising formulation for bacteria targeted delivery and immunity defensive system through macrophage improving uptake of bacteria, biodistribution, in vitro and in vivo antibacterial efficacy against MRSA.

     

Patient- and physician-related risk factors for hyperkalaemia in potassium-increasing drug–drug interactions

Purpose

Hyperkalaemia due to potassium-increasing drug–drug interactions (DDIs) is a clinically important adverse drug event. The purpose of this study was to identify patient- and physician-related risk factors for the development of hyperkalaemia.

Methods

The risk for adult patients hospitalised in the University Hospital Zurich between 1 December 2009 and 31 December 2011 of developing hyperkalaemia was correlated with patient characteristics, number, type and duration of potassium-increasing DDIs and frequency of serum potassium monitoring.

Results

The 76,467 patients included in this study were prescribed 8,413 potentially severe potassium-increasing DDIs. Patient-related characteristics associated with the development of hyperkalaemia were pulmonary allograft [relative risk (RR) 5.1; p?<?0.0001), impaired renal function (RR 2.7; p?<?0.0001), diabetes mellitus (RR 1.6; p?=?0.002) and female gender (RR 1.5; p?=?0.007). Risk factors associated with medication were number of concurrently administered potassium-increasing drugs (RR 3.3 per additional drug; p?<?0.0001) and longer duration of the DDI (RR 4.9 for duration ≥6 days; p?<?0.0001). Physician-related factors associated with the development of hyperkalaemia were undetermined or elevated serum potassium level before treatment initiation (RR 2.2; p?<?0.001) and infrequent monitoring of serum potassium during a DDI (interval >48 h: RR 1.6; p?<?0.01).

Conclusion

Strategies for reducing the risk of hyperkalaemia during potassium-increasing DDIs should consider both patient- and physician-related risk factors.     

Multi-Compartmental Vaccine Delivery System for Enhanced Immune Response to gp100 Peptide Antigen in Melanoma Immunotherapy

Purpose

To develop a multi-compartmental vaccine delivery system for safe and efficient delivery of the gp100 peptide antigen in melanoma immunotherapy.

Methods

Water-in-oil-in-water (W/O/W) multiple emulsion-based multi-compartmental vaccine delivery system containing the gp100 peptide was prepared by a two-step emulsification method. In vivo prophylactic and active immunization effectiveness of the novel squalane oil-containing gp100 vaccine was evaluated in the murine B16 melanoma model and compared with that of an incomplete Freund’s adjuvant (IFA)-based vaccine.

Results

Morphological evaluation of the W/O/W multiple emulsions showed that the oil-droplets were homogenously dispersed with the gp100 peptide encapsulated in an inner aqueous phase. Immunization with the gp100 peptide delivered in the W/O/W multiple emulsions-based vaccine resulted in increased protection against tumor challenge compared to IFA-based vaccine (p?<?0.05, n?=?8) signifying induction of enhanced anti-tumor immunity. In addition, serum Th1 cytokine levels and immuno-histochemistry of excised tumor tissues indicated activation and local infiltration of antigen specific cytotoxic T-lymphocytes into and/or surrounding the tumor mass. Moreover, the newly developed vaccine formulation did not induce any overt systemic toxicity.

Conclusion

Novel W/O/W multiple emulsions-based vaccine efficiently delivers the gp100 peptide antigen to induce cell-mediated anti-tumor immunity and offers an alternate, safe vaccine delivery system.     

Long-term neurocognitive effects of antipsychotics in schizophrenia: a network meta-analysis

Purpose

Most schizophrenic patients have mild to moderate cognitive impairment in the early stages of schizophrenia. The aim was to compare the long-term effects of various antipsychotic drugs on overall cognition and on specific cognitive domains in patients with schizophrenia or related disorders.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials in which oral formulations of second-generation antipsychotic drugs were compared head-to-head or against placebo or against haloperidol. Trials had to be of at least 6 months duration to be included. We used a network meta-analysis to combine direct and indirect comparisons of the cognitive effects between antipsychotics.

Results

Nine studies were eligible. The median trial duration was 52 weeks. Quetiapine, olanzapine and risperidone had better effects on global cognitive score than amisulpride (p?<?0.05) and haloperidol (p?<?0.05). When memory tasks were considered, ziprasidone had better effect than amisulpride (0.28 [0.02–0.54]) and haloperidol (0.32 [0.09–0.55]). Quetiapine was better than other drugs (p?<?0.001) on attention and processing speed tasks, followed by ziprasidone (p?<?0.05) and olanzapine (p?<?0.05). The effects of quetiapine, risperidone and olanzapine were better than those of amisulpride (p?<?0.05) on executive functions.

Conclusions

Our results suggest differences between antipsychotics in their effect on the overall cognitive score in schizophrenia. Quetiapine and olanzapine had the most positive effects, followed by risperidone, ziprasidone, amisulpride and haloperidol in that order. Significant differences were also observed according to specific cognitive tasks.     

Comparison of In Vitro Deposition of Pharmaceutical Aerosols in an Idealized Child Throat with In Vivo Deposition in the Upper Respiratory Tract of Children

Purpose

Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition.

Methods

In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered.

Results

In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2?±?2.3% of delivered dose) compared well (p?>?0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8?±?12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0?±?1.5%) matched in vivo extrathoracic deposition (p?>?0.05) in 6 to 16 year old children with cystic fibrosis (70.4?±?21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR.

Conclusions

The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.     

The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients

Rationale

We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine’s weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.

Method

Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.

Results

In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p?<?0.05) and leptin (p?<?0.05) levels, and elevation in cortisol (p?<?0.05) and DHEA (p?<?0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.

Conclusions

Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio–metabolic morbidity merits further large-scale, long-term investigation.     

Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons

Rationale

The various α subtypes of GABA_A receptors have been strongly implicated in alcohol reinforcement and consumption.

Objectives

The effects of the GABA_A α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on seeking and self-administration responses were evaluated in two groups of baboons trained under a 3-component chained schedule of reinforcement (CSR).

Methods

Alcohol (4 %?w/v; n?=?5; alcohol group) or a preferred nonalcoholic beverage (n?=?4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). 3-PBC (1.0–30.0 mg/kg) and saline were administered before drinking sessions under both acute and 5-day dosing conditions.

Results

Repeated, and not acute, doses of 3-PBC significantly decreased total self-administration responses (p?<?0.05), volume consumed (p?<?0.05), and gram per kilogram of alcohol (p?<?0.05) in the alcohol group. In the control group, 5-day administration of 3-PBC significantly decreased total self-administration responses (p?<?0.05) but produced nonsignificant decreases in volume consumed. Within-session pattern of drinking was characterized by a high level of drinking in the first 20 min of the session for both groups, which was significantly (p?<?0.05) decreased by all doses of 3-PBC (1.0–18.0 mg/kg) only in the alcohol group. In contrast, the first drinking bout in the control group was only reduced at the highest doses of 3-PBC (10.0 and 18.0 mg/kg).

Conclusions

The results support the involvement of the GABA_A α1 subtype receptor in alcohol reinforcement and consumption.     

Effects of caffeine and alcohol on mood and performance changes following consumption of lager

Rationale

The present study examined whether caffeine would modify the behavioural effects of alcohol.

Objectives

The aim of the study was to determine whether caffeine modifies the effects of alcohol on mood and psychomotor performance and to identify possible dose–response and temporal relationships.

Methods

A double-blind study examined the effects of three successive lager drinks (330 ml each) in the early afternoon on mood and psychomotor performance assessed at 30-min intervals over a 2-h period. Participants carried out a baseline session and were then randomly assigned to one of six conditions formed by combining three different doses of caffeine (0, 62.5 and 125 mg per drink) with either no alcohol or 4.3 % alcohol. One hundred and forty-six young adults (65 male, 81 female; age range 18–30 years) participated in the study. Mood (alertness, hedonic tone and anxiety) was assessed before and after performing simple reaction time and choice reaction time tasks.

Results

Alcohol was associated with higher hedonic tone (p?<?0.005), reduced anxiety (p?<?0.05) and reduced alertness (p?<?0.005). Caffeine had no modifying effect on hedonic tone or anxiety. However, the highest dose of caffeine did remove the effect of alcohol on alertness (p?<?0.05). Effects of alcohol and caffeine were found on the performance tasks (all p values?<?0.05) but these were independent effects.

Conclusions

The results from the present study confirm that caffeine does not remove the negative effects of alcohol on performance although high doses counteract the drop in subjective alertness produced by alcohol.     

Near-Infrared Image-Guided Delivery and Controlled Release Using Optimized Thermosensitive Liposomes

Purpose

To engineer optimized near-infrared (NIR) active thermosensitive liposomes to potentially achieve image-guided delivery of chemotherapeutic agents.

Methods

Thermosensitive liposomes were surface-coated with either polyethylene glycol or dextran. Differential scanning calorimetry and calcein release studies were conducted to optimize liposomal release, and flow cytometry was employed to determine the in vitro macrophage uptake of liposomes. Indocyanine green (ICG) was encapsulated as the NIR dye to evaluate the in vivo biodistribution in tumor-bearing mice.

Results

The optimized thermosensitive liposome formulation consists of DPPC, SoyPC, and cholesterol in the 100:50:30 molar ratio. Liposomes with dextran and polyethylene glycol demonstrated similar thermal release properties; however in vitro macrophage uptake was greater with dextran. Non-invasive in vivo NIR imaging showed tumor accumulation of liposomes with both coatings, and ex vivo NIR imaging correlated well with actual ICG concentrations in various organs of healthy mice.

Conclusions

The optimized thermosensitive liposome formulation demonstrated stability at 37?°C and efficient burst release at 40 and 42?°C. Dextran exhibited potential for application as a surface coating in thermosensitive liposome formulations. In vivo studies suggest that liposomal encapsulation of ICG permits reliable, real-time monitoring of liposome biodistribution through non-invasive NIR imaging.     

Evaluation of Poly (1, 6-bis-(p-carboxyphenoxy) Hexane-co-sebacic Acid Microspheres for Controlled Basal Insulin Delivery

Purpose

To develop poly 1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid (p(CPH/SA)) microspheres for controlled basal insulin delivery and evaluate their in vivo efficacy and toxicity.

Methods

A series of CPH/SA copolymers with molar ratios 20/80, 40/60, and 50/50 were synthesized and characterized. The stability of encapsulated insulin and the fraction of insulin released from microspheres were assessed by different analytical techniques. The skin from the injection site of rats was examined microscopically for histomorphological changes.

Results

Increasing the molar ratio of CPH/SA significantly (p?<?0.05) improved insulin loading and controlled insulin release. However, dimer aggregates of insulin were observed as CPH/SA molar ratio increased. Co-encapsulation of zinc oxide with insulin inhibited dimer aggregate formation and further controlled insulin release. Insulin was stable after entrapment into microspheres and during in vitro release studies. Administration of microsphere formulations CPH/SA 40/60 and 50/50 with zinc oxide controlled insulin release and maintained basal insulin levels for 42 days in rats. Skin sections showed minimal inflammation with no evidence for histomorphological changes and toxicity.

Conclusions

Insulin-loaded CPH/SA microspheres demonstrated considerable potential as controlled delivery system for insulin. Copolymer microspheres maintained basal insulin levels for 42 days and were biodegradable and biocompatible.     

Effect of a single-dose rifampin on the pharmacokinetics of pitavastatin in healthy volunteers

Purpose

As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers.

Methods

Twelve Chinese healthy male volunteers took 4 mg pitavastatin orally with 150 ml water or with a single dose of 600 mg rifampin on separate occasions and the plasma concentrations of pitavastatin were measured over 48 h by HPLC-MS/MS.

Results

A single dose of rifampin significantly increased the mean area under the plasma concentration-time curve(AUC)_(0-48h) and C_max of pitavastatin by 573.5 %(95%CI, 373.3–773.7 %, p?<?0.001) and 819.2 %(95 % CI, 515.4–1123.0 %, p?<?0.001) respectively, while significantly decreased the t_1/2 and CL/F of pitavastatin by 38.8 % (95 % CI, 18.2–59.4 %, p?<?0.001) and 81.4 % (95 % CI, 75.0–87.7 %, p?<?0.001) respectively.

Conclusions

Co-administration of pitavastatin with a single dose of rifampin resulted in a significant increase in plasma levels of pitavastatin in Chinese healthy subjects.     

Efficacy analysis of hydroxychloroquine therapy in systemic lupus erythematosus: a study on disease activity and immunological biomarkers

Background

Hydroxychloroquine (HCQ) is a widely prescribed medication to patients with systemic lupus erythematosus (SLE), with potential anti-inflammatory effects. This study was performed to investigate the efficacy of HCQ therapy by serial assessment of disease activity and serum levels of proinflammatory cytokines in SLE patients.

Methods

In this prospective cohort study, 41 newly diagnosed SLE patients receiving 400 mg HCQ per day were included. Patients requiring statins and immunosuppressive drugs except prednisolone at doses lower than 10 mg/day were excluded. Outcome measures were assessed before commencement of HCQ therapy (baseline visit) as well as in two follow-up visits (1 and 2 months after beginning the HCQ therapy). Serum samples of 41 age-matched healthy donors were used as controls.

Results

Median levels of IL-1β (p?<?0.001), IL-6 (p?=?0.001), and TNF-α (p?<?0.001) were significantly higher, whereas, median CH50 level was significantly lower (p?<?0.001) in SLE patients compared with controls. Two-month treatment with HCQ resulted in significant decrease in SLEDAI-2K (p?<?0.001), anti-dsDNA (p?<?0.001), IL-1β (p?=?0.003), IL-6 (p?<?0.001) and TNF-α (p?<?0.001) and a significant increase in CH50 levels (p?=?0.012). The reductions in SLEDAI-2K and serum levels of IL-1β and TNF-α were significantly greater in the first month compared with the reductions in the second month.

Conclusion

HCQ therapy is effective on clinical improvement of SLE patients through interfering with inflammatory signaling pathways, reducing anti-DNA autoantibodies and normalizing the complement activity.

     

RAFTsomes Containing Epitope-MHC-II Complexes Mediated CD4+ T Cell Activation and Antigen-Specific Immune Responses

Purpose

To develop a liposome formulation incorporating antigen-presenting cells (APCs) membrane microdomains with enriched epitope/MHC complexes to evaluate the activities of these liposomes (RAFTsomes) to activate T cells and prime immune responses.

Methods

We isolated membrane microdomain structures that contained the epitope/MHC complexes from ovalbumin (OVA) primed dendritic cells (DCs), and reconstituted them on liposomes surface by detergent dialysis. The resulted RAFTsomes were purified by density gradient centrifugation. Their T cell activation functions were evaluated by IL-2 secreting and proliferation assays in vitro. In vivo immune responses and the protective effect against OVA expressing EG.7 tumor challenge were also examined.

Results

Membrane microdomains containing enriched epitope/MHC complexes can be reconstituted into liposomes with defined size and composition. The integrity and activities of these complexes after reconstitution were confirmed by in vitro T cell assays. OVA epitope loaded RAFTsomes injected in vivo resulted in high anti-OVA IgG production (predominantly IgG1). The immunized mice were protected from EG.7 tumor cell inoculation challenge.

Conclusions

Based on these findings, we propose that RAFTsomes can be prepared with unique properties that may be used as an antigen delivery system for immunotherapeutic applications.     

Low BDNF is associated with cognitive deficits in patients with type 2 diabetes

Objective

Studies suggest that brain-derived neurotrophic factor (BDNF) plays an essential role in regulating memory-related neuroplasticity in the hippocampus. Type 2 diabetes (T2DM) is associated with impairment in many domains of cognitive function which may result from reduced BDNF; however, the correlation of BDNF with cognitive impairment in T2DM has not been investigated.

Materials and methods

We compared 208 patients with T2DM to 212 normal controls on serum BDNF and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Results

Serum BDNF levels were significantly decreased in T2DM patients compared to normal controls (p?<?0.001). The total score and nearly all indexes (all p?<?0.01) except for attention and visuospatial/constructional indexes (all p?>?0.05) of RBANS were markedly lower in T2DM than controls. There was a positive relationship between serum BDNF and delayed memory in patients with T2DM.

Conclusion

Our results suggest that BDNF may play a role in the pathophysiology of cognitive deficits, especially delayed memory in T2DM.     

Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial

Rationale

Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer’s disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI).

Objectives

This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI.

Methods

This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n?=?18) or placebo (n?=?18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate.

Results

The fish oil group showed significant improvement in short-term and working memory (F?=?9.890; ηp ²?=?0.254; p?<?0.0001), immediate verbal memory (F?=?3.715; ηp ²?=?0.114; p?<?0.05) and delayed recall capability (F?=?3.986; ηp ²?=?0.121; p?<?0.05). The 12-month change in memory (p?<?0.01) was significantly better in the fish oil group. Fish oil consumption was well tolerated, and the side effects were minimal and self-limiting.

Conclusions

This study suggested the potential role of fish oil to improve memory function in MCI subjects. Studies with larger sample sizes, longer intervention periods, different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made.     

Tacrolimus Loaded PEG-Cholecalciferol Based Micelles for Treatment of Ocular Inflammation

Purpose

Poor corneal permeability, nasolacrimal drainage and requirement of chronic administration are major drawbacks of existing therapies for ocular inflammation. Hence, we designed topical micelles of PEG₂₀₀₀ conjugated with cholecalciferol (PEGCCF).

Methods

Integrin targeted tacrolimus loaded PEGCCF micelles (TTM) were prepared by solvent diffusion evaporation method and characterized for particle size, osmolality, encapsulation efficiency and drug loading. Therapeutic potential of TTM was evaluated in benzalkonium chloride induced ocular inflammation model in BALB/c mice. Corneal flourescein staining and histopathological analysis of corneal sections was performed.

Results

TTM had a particle size of 45.3?±?5.3 nm, encapsulation efficiency (88.7?±?0.9%w/w) and osmolality of 292–296 mOsmol/Kg. TTM significantly reduced the corneal fluorescence as compared to tacrolimus suspension (TACS). H&E staining showed that TTM could restore corneal epithelial thickness, reduce stromal edema (p?<?0.05) and decrease number of inflammatory cells (p?<?0.01) compared with TACS. Immunohistochemistry analysis demonstrated lower expression of Ki67?+?ve cells (p?<?0.05) and IL-6 throughout the cornea against TACS (p?<?0.01) and the control (p?<?0.001).

Conclusions

TTM is an innovative delivery system for improving ocular inflammation due to a) integrin targeting b) PEGCCF in the form of carrier and c) anti-inflammatory and synergistic effect (due to Pgp inhibition) with TAC.