Molecular targets in cerebral malaria for developing novel therapeutic strategies.

Cerebral malaria (CM) is the severe neurological complication associated with Plasmodium falciparum infection. In clinical settings CM is predominantly characterized by fever, epileptic seizures, and asexual forms of parasite on blood smears, coma and even death. Cognitive impairment in the children and adults even after survival is one of the striking consequences of CM. Poor diagnosis often leads to inappropriate malaria therapy which in turn progress into a severe form of disease. Activation of multiple cell death pathways such as Inflammation, oxidative stress, apoptosis and disruption of blood brain barrier (BBB) plays critical role in the pathogenesis of CM and secondary brain damage. Thus, understanding such mechanisms of neuronal cell death might help to identify potential molecular targets for CM. Mitigation strategies for mortality rate and long-term cognitive deficits caused by existing anti-malarial drugs still remains a valid research question to ask. In this review, we discuss in detail about critical neuronal cell death mechanisms and the overall significance of adjunctive therapy with recent trends, which provides better insight towards establishing newer therapeutic strategies for CM.

Prospective of managing impaired brain insulin signalling in late onset Alzheimers disease with excisting diabetic drugs.

Late onset Alzheimer's disease (AD) is the most common cause of dementia among elderly. The exact cause of the disease is until now unknown and there is no complete cure for the disease. Growing evidence suggest that AD is a metabolic disorder associated with impairment in brain insulin signalling. These findings enriched the scope for the repurposing of diabetic drugs in AD management. Even though many of these drugs are moving in a positive direction in the ongoing clinical studies, the extent of the success has seen to influence by several properties of these drugs since they were originally designed to manage the peripheral insulin resistance. In depth understandings of these properties is hence highly significant to optimise the use of diabetic drugs in the clinical management of AD; which is the primary aim of the present review article.

Pluronic lecithin organogel of 5-aminosalicylic acid for wound healing.

5-Aminosalicylic acid (5-ASA) is an aminosalicylate anti-inflammatory drug, which is also known as mesalazine or mesalamine. Currently employed in treating inflammatory bowel disease, ulcerative colitis, inflamed anus or rectum, and maintain remission in Crohn's disease. Evidence from the researchers highlighted its significant re-epithelization in allergic asthma, aphthous, and gastric ulcerative conditions. The objective of the study was to formulate the pluronic lecithin organogel (PLO) containing 5-ASA and evaluate its wound-healing ability in a full thickness excision wound rat model. The data obtained from in silico docking studies revealed 5-ASA is having an affinity towards the transforming growth factor-beta (TGF-ß) specifically towards beta1. Among various formulations prepared (F1 to F8), F1, and F6 have shown a maximum in vitro drug release with optimum pH and viscosity. From MTT assay it was found that selected PLO formulations showed no toxicity and enhanced cell proliferation in HaCaT cell lines. In vivo wound-healing studies in albino Wistar rats has revealed that PLO accelerates wound closure and reepithelization to the statistically significant level on day 3 (p < .05) in comparison with untreated wounds. In conclusion, the overall results suggest that 5-ASA PLO gel is a potential therapeutic option for the treatments of wounds, however, further studies are highly warrened to determine the various mechanisms of 5-ASA in regulating the cell migration and reepithelization in wound healing to outspread its use in clinics.

Ameliorating the in vivo antimalarial efficacy of artemether using nanostructured lipid carriers.

Cerebral malaria (CM) is a fatal neurological complication of Plasmodium falciparum infection that affects children (below five years old) in sub-Saharan Africa and adults in South-East Asia each year having the fatality rate of 10-25%. The survivors of CM also have high risk of long term neurological or cognitive deficits. The objective of the present investigation was to develop optimised nanostructured lipid carriers (NLCs) of artemether (ARM) for enhanced anti-malarial efficacy of ARM. NLCs of ARM were prepared by a combination of high speed homogenisation (HSH) and probe sonication techniques. Preliminary solubility studies for ARM showed highest solubility in trimyristin (solid lipid), capmul MCM NF (liquid lipid) and polysorbate 80 (surfactant). Trimyristin and capmul showed superior miscibility at a ratio of 70:30.The optimised NLC formulation has the particle size (PS) of: 48.59 ± 3.67 nm, zeta potential (ZP) of: -32 ± 1.63 mV and entrapment efficiency (EE) of: 91 ± 3.62%. In vitro cell line (human embryonic kidney fibroblast cell line (HEK 293 T)) cytotoxicity studies showed that prepared formulation was non-toxic. The results of in vivo studies in CM induced mice prevented the recrudescence of parasite after administration of NLCs of ARM. Additionally, NLCs of ARM showed better parasite clearance, higher survival (60%) in comparison to ARM solution (40%). Also it was observed that lesser entrapment of Evans blue stain (prepared in PBS as solution) in the NLCs of ARM treated brains of C57BL/6 mice than ARM solution treated mice. Hence NLCs of ARM may be a better alternative for improving therapeutic efficacy than ARM solution.

Optimisation of chloroquine phosphate loaded nanostructured lipid carriers using Box-Behnken design and its antimalarial efficacy.

Chloroquine was once the most widely used antimalarial for nearly eight decades for its safety, efficiency, stability, low cost and finally for its less toxic nature. But its use and efficacy got slowly decreased with the increase of chloroquine resistant strains of Plasmodium species throughout the world. Lipid based nanodrug delivery systems have been very popular in the recent times as they are very less toxic, have drug targeting capabilities and also reduces the dosing frequency by increasing efficacy of the drug. In the present research work, response surface methodology was employed to optimise chloroquine phosphate (CQ) loaded nanostructured lipid carriers (NLCs) using a modified double emulsion technique. The optimised CQ loaded NLC showed a particle size of 66.50 ± 1.21 nm, PDI of 0.210 ± 0.016, ZP of +38.4 ± 1.44 and EE of 78.2 ± 1.2%, respectively. The in vitro and in vivo antimalarial studies of CQ loaded NLCs showed an enhanced antimalarial efficacy of the nanoformulation with a better suppression of parasitemia and with an increased efficacy of more than 23% in comparison to pure drug. This study demonstrated that by loading a drug into an NLCs system can help in overcoming the problems associated with the present antimalarials available.

Design, characterization and antimalarial efficacy of PEGylated galactosylated nano lipid carriers of primaquine phosphate.

This study was aimed to design and optimize primaquine phosphate (PQ) loaded nanostructured lipid carriers (NLCs) using response surface methodology. The optimized NLCs were evaluated for various physical and morphological characterizations. The in vitro studies for drug release showed that PQ loaded NLCs had a sustained release up to 72 h and the stability studies confirmed that the PQ-NLCs were stable for 90 d at 4 °C and 25 °C. In vitro erythrocyte toxicity revealed that PQ-NLCs were less toxic than the pure drug. In vitro parasite growth inhibition assay showed an IC50 value of 71.11 ± 6.47 ng/ml for the 3D7 Plasmodium falciparum (CQ sensitive) strain and 263.86 ± 5.68 ng/ml for RKL9 P. falciparum (CQ resistant) strain for the PQ-NLCs. Enhanced parasitaemia suppression of 99.46% at 2 mg/kg/d, a better suppression of parasitaemia of about 28% more than pure drug and a higher survivality rate of 66.66% even after the 35th day was observed for the PQ loaded NLCs. Also from the comparative fluorescent imaging study, it was clearly observed that accumulation of PQ-NLCs in the liver was more that of the pure drug. These results clearly indicated that the limitations of antimalarial drug PQ can be overcomed by loading it into the NLCs.

Malaria treatment using novel nano-based drug delivery systems.

We reside in an era of technological innovation and advancement despite which infectious diseases like malaria remain to be one of the greatest threats to the humans. Mortality rate caused by malaria disease is a huge concern in the twenty-first century. Multiple drug resistance and nonspecific drug targeting of the most widely used drugs are the main reasons/drawbacks behind the failure in malarial therapy. Dose-related toxicity because of high doses is also a major concern. Therefore, to overcome these problems nano-based drug delivery systems are being developed to facilitate site-specific or target-based drug delivery and hence minimizing the development of resistance progress and dose-dependent toxicity issues. In this review, we discuss about the shortcomings in treating malaria and how nano-based drug delivery systems can help in curtailing the infectious disease malaria.