Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy

Objective

The objective of the research was to formulate and evaluate sumatriptan succinate-loaded chitosan nanoparticles for migraine therapy in order to improve its therapeutic effect and reduce dosing frequency.

Material and Methods

The Taguchi method design of experiments (L9 orthogonal array) was applied to obtain the optimized formulation. The sumatriptan succinate-loaded chitosan nanoparticles (CNPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and Tween 80 as surfactant.

Results

The CNPs had a mean size of 306.8 ± 3.9 nm, a zeta potential of +28.79 mV, and entrapment efficiency of 75.4 ± 1.1%. The in vitro drug release of chitosan nanoparticles was evaluated in phosphate buffer saline pH 5.5 using goat nasal mucosa and found to be 76.7 ± 1.3% within 28 hours.

Discussion

The release of the drug from the nanoparticles was anomalous, showing non-Fickian diffusion indicating that drug release is controlled by more than one process i.e. the superposition of both phenomena, a diffusion-controlled as well as a swelling-controlled release. This is clearly due to the characteristics of chitosan which easily dissolves at low pH, thus a nasal pH range of 5.5 ± 0.5 supports it very well. The mechanism of pH-sensitive swelling involves protonation of the amine groups of chitosan at low pH. This protonation leads to chain repulsion, diffusion of protons and counter ions together with water inside the gel, and the dissociation of secondary interactions.

Conclusion

The results suggest that sumatriptan succinate-loaded chitosan nanoparticles are the most suitable mode of drug delivery for promising therapeutic action.     

Paclitaxel-loaded PLGA nanoparticles surface modified with transferrin and Pluronic®P85, an in vitro cell line and in vivo biodistribution studies on rat model

The development of multidrug resistance (due to drug efflux by P-glycoproteins) is a major drawback with the use of paclitaxel (PTX) in the treatment of cancer. The rationale behind this study is to prepare PTX nanoparticles (NPs) for the reversal of multidrug resistance based on the fact that PTX loaded into NPs is not recognized by P-glycoproteins and hence is not effluxed out of the cell. Also, the intracellular penetration of the NPs could be enhanced by anchoring transferrin (Tf) on the PTX-PLGA-NPs. PTX-loaded PLGA NPs (PTX-PLGA-NPs), Pluronic^®P85-coated PLGA NPs (P85-PTX-PLGA-NPs), and Tf-anchored PLGA NPs (Tf-PTX-PLGA-NPs) were prepared and evaluted for cytotoxicity and intracellular uptake using C6 rat glioma cell line. A significant increase in cytotoxicity was observed in the order of Tf-PTX-PLGA-NPs > P85-PTX-PLGA-NPs > PTX-PLGA-NPs in comparison to drug solution. In vivo biodistribution on male Sprague–Dawley rats bearing C6 glioma (subcutaneous) showed higher tumor PTX concentrations in animals administered with PTX-NPs compared to drug solution.     

Formulation and Optimization of a Sustained-Release Tablet of Ketorolac Tromethamine

The objective of our study was to formulate a sustained-release tablet of Ketorolac tromethamine, which is a nonsteroidal anti-inflammatory agent. A 2 3 full factorial design (8 runs) was selected. The variables studied were the amount of drug (30 and 40 mg), ratio of hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC) (240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-controlled matrix tablets were manufactured by direct compression of formulation ingredients using a Stokes single punch tablet press. Dissolution tests were performed using USP apparatus 3 (Bio-Dis II), at various pHs to mimic the conditions that exist in the gastrointestinal tract. Responses studied included time for 50% of the drug to dissolve (T 50), diffusional exponent (n) that characterizes the release mechanism, and percent friability of the tablets. Analysis of variance indicated that the release rate (T 50) was affected by the HPMC/NaCMC ratio, amount of drug, and two-way and three-way interactions; whereas the amount of drug, HPMC/NaCMC ratio, ethylcellulose, and the interaction between drug and HPMC/NaCMC and HPMC/NaCMC and ethylcellulose and also three-way interactions were significantly affecting the diffusional exponent (n) . The release mechanism was found to be super-case II transport. The friability of the tablets was significantly affected by all three factors: amount of drug, HPMC/NaCMC ratio, and amount of ethylcellulose. The formulation giving the best release characteristics was identified.     

A Profile for Predicting Attrition from Exercise in Older Adults

The purpose of this study was to determine a profile for predicting attrition among older adults involved in a 12-month exercise program. The parent study was a single-blinded randomized controlled trial. The study took place between 2006 and 2009 within a university setting. Older adults (N?=?179) completed baseline assessments of functional performance and psychosocial measures. Participants who were randomized, elected to receive treatment, and did not complete the exercise program were considered “dropouts” (n?=?35). Those who completed the program (n?=?144) were classified as “completers.” A latent profile analysis revealed two distinct patterns of memory complaints, self-efficacy to overcome barriers to exercise, balance performance, and stair performance. Dropouts were nearly twice as likely to be members of the profile that exhibited a higher degree of memory complaints, lower self-efficacy for overcoming exercise barriers, poorer single leg balance, and longer times to walk down stairs. The results provide an initial validation of a profile for discriminating between “dropouts” and “completers,” one that may have considerable utility for screening older adults prior to study entry.     

The Structure of Glycosaminoglycans and their Interactions with Proteins

Glycosaminoglycans (GAGs) are important complex carbohydrates that participate in many biological processes through the regulation of their various protein partners. Biochemical, structural biology and molecular modelling approaches have assisted in understanding the molecular basis of such interactions, creating an opportunity to capitalize on the large structural diversity of GAGs in the discovery of new drugs. The complexity of GAG–protein interactions is in part due to the conformational flexibility and underlying sulphation patterns of GAGs, the role of metal ions and the effect of pH on the affinity of binding. Current understanding of the structure of GAGs and their interactions with proteins is here reviewed: the basic structures and functions of GAGs and their proteoglycans, their clinical significance, the three‐dimensional features of GAGs, their interactions with proteins and the molecular modelling of heparin binding sites and GAG–protein interactions. This review focuses on some key aspects of GAG structure–function relationships using classical examples that illustrate the specificity of GAG–protein interactions, such as growth factors, anti‐thrombin, cytokines and cell adhesion molecules. New approaches to the development of GAG mimetics as possible new glycotherapeutics are also briefly covered.     

Decreasing Oxidative Stress with Choline and Carnitine in Women

Objective: Fatty acid oxidation is predominantly a mitochondrial event, which is enhanced by dietary choline and carnitine supplementation resulting in extra reactive oxygen species (ROS) load. The objective was to assess oxidative stress level by thiobarbituric acid reactive substances [TBARS] in choline and carnitine supplemented healthy women before and after mild exercise.

Methods: Nineteen free-living women completed the placebo control study in which choline and/or L-carnitine was orally taken for 21 days. Anthropometric measurements, dietary recall, exercise routine and blood samples were analyzed to determine body composition, nutrients intake, distance walked and biochemical markers related to oxidative stress.

Results: TBARS were significantly lower in the groups supplemented with choline, carnitine or both and the mild exercise (walking) was not a deterrent in this effect of the supplements. Serum vitamin A and E concentrations were higher in the supplemented groups even though the consumption of these nutrients was not different among the groups.

Conclusion: Choline and carnitine supplementation lowers lipid peroxidation, and promotes conservation of retinol and α-tocopherol in free-living women.     

Opposite effects of dietary saturated and unsaturated fatty acids on ethanol-pharmacokinetics,triglycerides and carnitines.

The objective of this study was to determine the effects of saturated fatty acid (SFA) and unsaturated fatty acid (UFA) diets on ethanol pharmacokinetics. Hepatic ADH and plasma carnitines were also evaluated as possible indicators of the mechanism involved.

Sprague-Dawley male rats were fed modified AIN76 diets containing 10% coconut oil (SFA) or corn oil (UFA) for 120 days. A single dose (3 g/kg bw) of ethanol (13% solution) was orally administered using a gastric canula on day 30, 90, 105 and 120. Tail vein blood samples were collected at various intervals following ethanol dose and were analyzed for blood-ethanol concentration (BEC). In an analogous trial rats were given these diets for 70 days and blood samples were collected on day 35 and 63 for triglycerides, cholesterol and carnitine determination. The animals were killed on day 70 to collect liver for ADH determination.

Compared to the UFA group, the SFA group exhibited significantly higher BEC, larger area under the curve, longer half-life of ethanol, and lower rates of ethanol elimination. Plasma carnitines were also higher in the SFA vs UFA group. However, hepatic ADH activity was not different between the groups.

Dietary SFA protects liver from alcohol injury by retarding ethanol metabolism, and carnitine may be involved.     

Bridging Populations—Sexual Risk Behaviors and HIV Prevalence in Clients and Partners of Female Sex Workers,Bangkok, Thailand 2007

The aim of this study is to estimate HIV prevalence and assess sexual behaviors in a high-risk and difficult-to-reach population of clients of female sex workers (FSWs). A modified variation of respondent-driven sampling was conducted among FSWs in Bangkok, where FSWs recruited 3 FSW peers, 1 client, and 1 nonpaying partner. After informed consent was obtained, participants completed a questionnaire, were HIV-tested, and were asked to return for results. Analyses were weighted to control for the design of the survey. Among 540 FSWs, 188 (35%) recruited 1 client, and 88 (16%) recruited 1 nonpaying partner. Clients’ median age was 38 years. HIV prevalence was 20% and was associated with younger age at first sexual experience [relative risk (RR) = 3.10, 95% confidence interval (CI) 1.16–8.24] and condom use during last sexual encounter with regular partner (RR = 3.97, 95% CI 1.09–14.61). Median age of nonpaying partners was 34 years, and HIV prevalence was 15.1%. There were 56 discordant FSW–client pairs and 14 discordant FSW–nonpaying partner pairs. Condom use was relatively high among discordant FSW–client pairs (90.1%) compared to discordant FSW–nonpaying partner pairs (18.7%). Results suggest that sexual partners of FSWs have a high HIV prevalence and can be a bridge for HIV transmission to other populations. Findings also highlight the importance of initiating surveillance and targeted programs for FSW partners, and demonstrate a recruitment method for hard-to-reach populations.     

A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells

We have developed a procedure for the synthesis of N-hydroxy-N(1)-phenyloctanediamide (suberoylanilide hydroxamic acid (SAHA)), providing the product in 79.8% yield. SAHA is a potent inhibitor of histone deacetylase, induces differentiation and/or apoptosis in certain transformed cells in culture, and suppressed the growth of human prostate cancer LNCaP and PC-3 cell lines. The combination of SAHA with other compounds inhibited cell proliferation of LNCaP cells in additive fashion and resulted in synergistic growth inhibition.     

Choroidal Structural Changes in Tubercular Multifocal Serpiginoid Choroiditis

Purpose: To assess choroidal vascular changes among patients with tubercular multifocal serpiginoid choroiditis (TB MSC) using previously validated techniques.

Methods: Patients with TB MSC (n = 18) and healthy controls (n = 30) underwent enhanced-depth imaging optical coherence tomography (EDI-OCT) imaging. Using previously validated algorithm of image binarization, EDI-OCT scans were segmented to derive total choroidal area, luminal area, stromal area, and choroidal vascularity index (CVI).

Results: There was a statistically significant difference in the CVI between controls (66.90 ± 1.77%) and TB MSC patients (65.46 ± 2.53%; p < 0.001). There was significant reduction in CVI at follow-up (3 months) (63.77 ± 3.91%; p = 0.05). The choroidal thickness was higher in TB MSC compared to controls (278.90 ± 57.84 µm versus 329.33 ± 27.69 µm; p = 0.001).

Conclusions: CVI provides insight into structural changes in choroid in TB MSC. During the active disease, there is relative decrease in choroidal vascularity. As the lesions heal, choriocapillaris atrophy occurs with remodeling of choroid.