Nimbolide and isonimbolide

Nimbolide 1, a potent molecule of biological significance, was isolated. Attempts were made to cleave the ether linkage in nimbolide using boron trifluoride etherate in the presence of tetrabutyl ammonium bromide so as to generate a ring-opened structure akin to azadirachtins, which are known to possess excellent antifeedant properties. However, a novel rearranged product was envisaged during the course of the reaction, which was determined as isonimbolide 2—a structural isomer of nimbolide through spectroscopic methods.     

Substance use history in behavioral-variant frontotemporal dementia versus primary progressive aphasia

As older adults are prone to cognitive disorders, the interaction of the fields of substance use and misuse and cognitive neuroscience is an emerging area of research. Substance use has been reported in some subtypes of frontotemporal dementia, such as behavioral variant frontotemporal dementia. However, characterization of substance use in other subtypes of frontotemporal dementia, such as primary progressive aphasia, is unknown. The objective of this baseline analysis was to explore whether any measures of substance use history differed significantly among behavioral variant frontotemporal dementia (n = 842) and primary progressive aphasia (n = 526) in a large national dataset. The National Alzheimer's Coordinating Center's Uniform Data Set study is a national dataset that collects data on patients with various cognitive disorders and includes some questions on substance use. Each substance use variable was used as the outcome and the frontotemporal dementia subtype as the predictor. Total years smoked cigarettes, age when last smoked cigarettes, average number of packs/day smoked when participants smoked, and any recent, remote, or combined recent/remote history of alcohol abuse or drug abuse did not significantly differ between the behavioral variant frontotemporal dementia and primary progressive aphasia subtypes (all p-values > .001). A significantly greater percentage of participants smoked in the last 30 days in the behavioral variant frontotemporal dementia subtype (10.4%, n = 834) compared to the primary progressive aphasia subtype (3.3%, n = 517; p < .001). Clinical providers in both the dementia and substance use fields are encouraged to screen for and monitor substance use in all frontotemporal dementia subtypes.     

Impact of residential medication management reviews on anticholinergic burden in aged care residents

Objectives:

The primary objective of this study was to investigate the impact of Residential Medication Management Reviews (RMMRs) on anticholinergic burden quantified by seven anticholinergic risk scales.

Design:

Retrospective analysis.

Setting:

Accredited pharmacists conducted RMMRs in aged-care facilities (ACFs) in Sydney, Australia.

Participants:

RMMRs pertained to 814 residents aged 65 years or older.

Measurements:

Anticholinergic burden was quantified using seven scales at baseline, after pharmacists’ recommendations and after the actual GP uptake of pharmacists’ recommendations. Change in the anticholinergic burden was measured using the Wilcoxon sign rank test.

Results:

At baseline, depending on the scale used to estimate the anticholinergic burden, between 36% and 67% of patients were prescribed at least one regular anticholinergic medication (ACM). Anticholinergic burden scores were significantly (p?<?0.001) lower after pharmacists’ recommendations as determined by each of the seven scales. The reduction in anticholinergic burden was also significant (p?<?0.001) after GPs’ acceptance of the pharmacists’ recommendations according to all scales with the exception of one scale which reached borderline significance (p?=?0.052).

Conclusion:

Despite the limitations of the retrospective design and differences in the estimation of anticholinergic burden, this is the first study to demonstrate that RMMRs are effective in reducing ACM prescribing in ACF residents, using a range of measures of anticholinergic burden. Future studies should focus on whether a decrease in anticholinergic burden will translate into improvement in clinical outcomes.     

Arylalkyl ketones, benzophenones, desoxybenzoins and chalcones inhibit TNF-α induced expression of ICAM-1: structure-activity analysis

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in the pathogenesis of various inflammatory and autoimmune diseases. Small molecules that block these interactions have been targeted as potential therapeutic agents against acute and chronic inflammatory diseases. In an effort to identify potent intercellular cell adhesion molecule-1 (ICAM-1) inhibitors, a large number of arylalkyl ketones, benzophenones, desoxybenzoins and chalcones and their analogs (54 in total) have been synthesized and screened for their ICAM-1 inhibitory activity. The structure-activity relationship studies of these compounds identified three potent chalcone derivatives and also demonstrated the possible mechanism for their ICAM-1 inhibitory activities. The most active compound was found to be 79.     

Evaluation of cytotoxic, oxidative stress, proinflammatory and genotoxic responses of micro- and nano-particles of dolomite on human lung epithelial cells A(549)

Dolomite is a natural mineral of great industrial importance and used worldwide, thus millions of workers are at risk of occupational exposure. Its toxicity is however, meagerly documented. In the present investigation, a dolomite powder obtained from its milling unit was analyzed by some standard methods namely, optical microscopy, transmission electron microscopy and dynamic light scattering. Results showed that dolomite powder contained particles of different shapes and size both microparticles (MPs) and nanoparticles (NPs), suggesting potential occupational exposure of these particles. An attempt was therefore, made to investigate dolomite toxicity in a particle size-dependent manner in human lung epithelial cells A(549). The comparative toxicity evaluation of MPs and NPs was carried out by assessing their effects on cell viability, membrane damage, glutathione, reactive oxygen species (ROS), lipid peroxidation (LPO), micronucleus (MN) and proinflammatory cytokines, namely tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). These markers of cytotoxicity, genotoxicity and inflammation were assayed in cells exposed to MPs and NPs in a dose-and time-dependent manner. Invariably, their toxic effects were dose-and time-dependent while NPs in general were significantly more toxic. Notably, NPs caused oxidative stress, genotoxicity and inflammatory responses, as seen by significant induction of ROS, LPO, MN, TNF-α, IL-1β and IL-6. Thus, the study tends to suggest that separate health safety standards would be required for micrometer and nanometer scale particles of dolomite.     

Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia

Dichlorvos [2,2-dichlorovinyl dimethyl phosphate] is one of the most common in-use organophosphate (OP) in developing nations. Previous studies from our lab have shown chronic Dichlorvos exposure leads to neuronal cell death in rats. However, the extent of damage caused by Dichlorvos to other cells of the central nervous system (CNS) is still not clear. Microglial cells are the primary threat sensors of CNS which become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by increased cellular damage in the affected regions. Using rat primary microglial cultures, here we show that Dichlorvos exposure can activate and induce apoptotic cell death in microglia. We observed significant up-regulation of pro-inflammatory molecules like nitric oxide, TNF-α, and IL-1β when microglia were treated with Dichlorvos (10 μM). Significant up-regulation of CD11b, microglial specific activation marker, was also observed after 24 h of Dichlorvos treatment. The activated microglial cells eventually undergo cell death after 48 h of Dichlorvos treatment. The DNA fragmentation pattern of Dichlorvos treated microglia along with increased expression of Bax in mitochondria, cytochrome c release from mitochondria, and caspase-3 activation led us to assume that microglia were undergoing apoptosis. Thus, the present study showed that Dichlorvos can induce microglial activation and ultimately apoptotic cell death. These findings gave new perspective to the current knowledge of Dichlorvos (OPs) mediated CNS damage and presents microglial activation as a potential therapeutic target for preventing the OP induced neuronal damage.     

Development and validation of HPLC method for vicenin-1 isolated from fenugreek seeds in rat plasma: application to pharmacokinetic,tissue distribution and excretion studies

Context: Vicenin-1, a flavonol glycoside, has potent platelet aggregation inhibition, antioxidant, radioprotectants and anti-inflammatory activities.

Objective: To establish a rapid, simple, precise and sensitive high-performance liquid chromatography (HPLC) method for determination of vicenin-1 in rat plasma, and to investigate the pharmacokinetics, tissue distribution and excretion after a single 60?mg/kg oral dose in rats.

Materials and methods: Vicenin-1 was extracted by solid–liquid extraction through Tulsicon^® ADS-400 (0.40–1.2?mm). Chromatographic separation was achieved by HPLC with a C₁₈ column with a mobile phase composed of water and acetonitrile (75:25 v/v) and a flow rate of 1?mL/min along with UV detection at 210?nm.

Results: Good linearity of calibration curve was found between 10.5 and 100.5?μg/mL (R^2?=^?0.995) for plasma and tissue, whereas 2.5–500?μg/mL (R^2?=^?0.999) for the urine and stool samples. The extraction recoveries were 98.51–99.58% for vicenin-1 in plasma, whereas intra-day and inter-day precision were validated by relative standard deviation (%RSD), that came in the ranges of 1.16–1.79% and 1.28–1.73%, respectively. The pharmacokinetics results showed C_max (7.039?μg/mL) and T_max (2?h) after oral administration of vicenin-1. Tissue distribution study showed that the highest concentration of vicenin-1 was achieved in the liver followed by the lung. Approximately 24.2% of its administered dose was excreted via urinary excretion route.

Conclusion: The first-pass metabolism, poor solubility and presence of reducing sugar moiety in vicenin-1 may decrease its bioavailability. The developed method is sensitive, specific and was successfully applied to the pharmacokinetics, tissue distribution and excretion studies of vicenin-1 in rats.     

Evaluating the inhibitory potential of Withania somnifera on platelet aggregation and inflammation enzymes: An in vitro and in silico study

Context Withania somnifera (L.) Dunal is traditionally used for treating various ailments, but lacks scientific evaluation.

Objective This study evaluates Withania somnifera (WS) for its effect on platelet activity and inflammatory enzymes.

Materials and methods Aqueous and ethanolic (1:1) leaf extracts were subjected to in vitro indirect haemolytic activity using Naja naja venom, human platelet aggregation was quantified for lipid peroxidation using arachidonic acid (AA) as agonist and 5-lipoxygenase (5-LOX) levels were determined using standard spectrometric assays. Further, molecular docking was performed by the ligand fit method using molegro software package (Molegro ApS, Aarhus, Denmark).

Results The study found that aqueous and ethanol extracts have very negligible effect (15%) with an IC₅₀ value of 13.8?mg/mL on PLA₂ from Naja naja venom. Further, extracts of WS also had very little effect (18%) with an IC₅₀ value of 16.6?mg/mL on malondialdehyde (MDA) formation. However, a 65% inhibition of 5-LOX with an IC₅₀ value of 0.92?mg/mL was observed in 1:1 ethanol extracts. The same was evident from SAR model with the active ingredient withaferin A binding predominantly on Phe 77, Tyr 98, Arg 99, Asp 164, Leu 168, Ser 382, Arg 395, Tyr 396 and Tyr 614 with an atomic contact energy value of??128.96 compared to standard phenidone (?103.61). Thus, the current study validates the application of WS for inflammatory diseases.

Conclusion This study reveals the inhibitory potential of W. somnifera on inflammatory enzymes and platelet aggregation. Thus, WS can serve as a newer, safer and affordable medicine for inflammatory diseases.     

Controlled release effervescent buccal discs of buspirone hydrochloride: in vitro and in vivo evaluation studies

Abstract

In the present study controlled release effervescent buccal discs of buspirone hydrochloride (BS) were designed using HPMC as rate controlling and bioadhesive polymer by direct compression method. Sodium bicarbonate and citric acid were used in varying amounts as effervescence forming agents. Carbon dioxide evolved due to reaction of sodium bicarbonate and citric acid was explored for its potential as buccal permeation enhancer. The designed buccal discs were evaluated for physical characteristics and in vitro drug release studies. Bioadhesive behavior of designed buccal discs was assessed using texture analyzer. In vivo animal studies were performed in rabbits to study bioavailability of BS in the designed buccal discs and to establish permeation enhancement ability of carbon dioxide. It was observed that effervescent buccal discs have faster drug release compared to non-effervescent buccal discs in vitro and effervescent buccal discs demonstrated significant increase in bioavailability of drug when compared to non-effervescent formulation. Hence, effervescent buccal discs can be used as an alternative to improve the drug permeation resulting in better bioavailability. However, the amount of acid and base used for generation of carbon dioxide should be selected with care as this may damage the integrity of bioadhesive dosage form.