Curcumin Prevents Acute Neuroinflammation and Long-Term Memory Impairment Induced by Systemic Lipopolysaccharide in Mice

Systemic lipopolysaccharide (LPS) induces an acute inflammatory response in the central nervous system (CNS) (\u201cneuroinflammation\u201d) characterized by altered functions of microglial cells, the major resident immune cells of the CNS, and an increased inflammatory profile that can result in long-term neuronal cell damage and severe behavioral and cognitive consequences. Curcumin, a natural compound, exerts CNS anti-inflammatory and neuroprotective functions mainly after chronic treatment. However, its effect after acute treatment has not been well investigated. In the present study, we provide evidence that 50 mg/kg of curcumin, orally administered for 2 consecutive days before a single intraperitoneal injection of a high dose of LPS (5 mg/kg) in young adult mice prevents the CNS immune response. Curcumin, able to enter brain tissue in biologically relevant concentrations, reduced acute and transient microglia activation, pro-inflammatory mediator production, and the behavioral symptoms of sickness. In addition, short-term treatment with curcumin, administered at the time of LPS challenge, anticipated the recovery from memory impairments observed 1 month after the inflammatory stimulus, when mice had completely recovered from the acute neuroinflammation. Together, these results suggest that the preventive effect of curcumin in inhibiting the acute effects of neuroinflammation could be of value in reducing the long-term consequences of brain inflammation, including cognitive deficits such as memory dysfunction

Natural Deep Eutectic Solvents (NADES) as a Tool for Bioavailability Improvement: Pharmacokinetics of Rutin Dissolved in Proline/Glycine after Oral Administration in Rats: Possible Application in Nutraceuticals

There is a need for innovation in plant-derived pharmaceuticals, food supplements and nutraceutical products regarding the use of more eco-sustainable solvents for their extraction. Furthermore, the poor oral bioavailability of several phytochemicals with health promoting effects stimulates the research in the field of pharmaceutical formulations. Natural Deep Eutectic Solvents (NADES) are formed by natural compounds, and can be considered as future solvents being especially useful for the preparation of nutraceuticals and food-grade extracts. In this paper various NADES were prepared using sugars, aminoacids and organic acids. Rutin (quercetin-3-O-\u3b1-l-rhamnopyranosyl-(1\u21926))-\u3b2-d-glucopyranose) was used as a model compound to study NADES. Moreover, the effect of various eutectic mixtures on rutin\u2019s water solubility was studied. Proline/glutamic acid (2:1) and proline/choline chloride (1:1) mixtures have a solubility comparable to ethanol. The proline/glutamic acid (2:1) eutectic containing rutin was used in a pharmacokinetic study in Balb/c mice while bioavailability was compared to oral dosing of water suspension. Plasmatic levels of rutin were measured by HPLC-MS/MS showing increased levels and longer period of rutin permanence in plasma of NADES treated animals. This paper reports the possible use of non-toxic NADES for pharmaceutical and nutraceutical preparations

Microbial inactivation efficiency of supercritical CO2drying process

Conventional drying of spices, as hot air treatment, often needs an additional downstream inactivation step to decrease the microbial load of the dried product and improve its microbial safety and microbial quality. In this regard, the present work explored the possibility to dry and decontaminate food in a single step using supercritical carbon dioxide (scCO(2)) as a drying agent. A case study was focused on the drying of herbs and the antimicrobial effects were evaluated on the naturally present microbiota. For this purpose, experiments were carried out on coriander leaves using a high pressure vessel at 10 MPa, at two different temperatures (40 and 50 degrees C) with drying time of 0 and 150 min to establish the influence of each parameter on the microbial inactivation. Yeasts and molds appeared to be the least resistant to scCO(2) as they could never be detected after the treatment (<2 log CFU/g). Mesophilic bacteria were also significantly reduced, up to 4 log CFU/g, but remained above the limit of quantification. The quality of the dried product was comparable with the quality of air-dried samples in terms of phenolic constituents. Overall, the results indicated that scCO(2) drying was a promising green drying technique combining both drying and microbial inactivation in a single step with a relevant impact on safety and costs

Pharmacokinetics and immunomodulatory effect of lipophilic Echinacea extract formulated in softgel capsules

An attractive herbal product, softgel capsules containing 10 mg of Echinacea angustifolia lipophilic extract, was given in a single oral administration to 10 human volunteers to perform a pharmacokinetic and immunological study. The plasma concentration of the major constituent was monitored, quantifying at predetermined time points the dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides (tetraene). The plasmatic levels of IL-2, IL-6, IL-8, IL-10 and TNF-a in samples collected before and 24 h after drug administration were analyzed by cytokine assay. The total RNA was extracted from limpho-monocyte isolated from the same blood samples and the same cytokines in terms of gene expression were evaluated. With the help of proper statistical tests the differences between the values obtained at 0 and 24 h were evaluated. Results of pharmacokinetic studies attest an approximately 3.5-fold improvement of tetraene oral bioavailability compared with previously published studies. Dodeca-2E,4E-dienoic acid isobutylamide exerts immunomodulatory effects down-regulating the gene expression and reducing the protein plasmatic levels of pro-inflammatory cytokines such as IL-6, TNF-a and IL-8, and up-regulating the expression of anti-inflammatory molecules as IL-10. Student\u2019s two-sided paired t-test and non-parametric Wilcoxon\u2013Mann\u2013Whitney signed rank test agree in the conclusions about the differences between the ln values at 24 h and corresponding ln values at 0 h

Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors

Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original per os formulation.Methods:In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. In vivo analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively per os FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared.Results:In vitro, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (P = 0.017 and P = 0.008, respectively). In vivo, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF; P &lt; 0.01 and P &lt; 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60min vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%; P &lt; 0.05) and improved pattern of flushing and nasal congestion.Conclusion: Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects

Retrospective analysis of a lactose breath test in a gastrointestinal symptomatic population of Northeast Italy: Use of (H2+2CH4) versus H2threshold

Background: Lactose malabsorption is normally evaluated by measuring exhaled H-2 produced by intestinal flora, from unabsorbed lactose. However, differing microbiome composition can lead to the production of CH4 instead of H-2; hence, some authors challenge the H-2 method sensitivity and favor the evaluation of both intestinal gases. Aim: To compare different approaches to usage of a lactose breath test for lactose malabsorption diagnosis, after medical evaluation of gastrointestinal symptoms. Methods: In a retrospective observational study, we compared the 2 approaches in a population of 282 subjects in Northern Italy. Following oral lactose administration, exhaled samples were harvested every 30 minutes for 4 hours and prepared for H-2 and CH4 analysis. Basal gas levels were subtracted from H-2 and CH4 ppm and values at 4 hours and peaks were considered for analysis. Results: Applying the standard methodology, which takes separately into consideration H-2 and CH4 produced in the intestinal lumen, the results indicated that 11.7% of the patients were diagnosed "positive" for hypolactasia, differently from what was expected. Conversely, taking into consideration the sum of H-2 and CH4, the percentage increased to 62.8%, closer to the expected one. No significant differences were found when comparing the 2 groups for age, gender, or symptoms. The sizable difference between the 2 approaches is likely linked to gut microbiome variability, and consequently the different production of the 2 gases, in the population. Conclusion: The threshold normally used for lactose breath test should be reconsidered and changed, merging H-2 and CH4 stoichiometric values to increase sensitivity

Echinacea angustifolia DC. Lipophilic Extract Patch for Skin Application: Preparation, In Vitro and In Vivo Studies

Dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) is the main component of Echinacea angustifolia DC. lipophilic extract, the bioavailability and immunomodulatory eect after oral administration in soft gel capsules in healthy volunteers of whichwehave already demonstrated. In the present work, we assessed the transdermal administration as an alternative route of administration of such an alkamide. The first step, therefore, encompassed the preparation of a drug-in-adhesive patch with an area of 868 mm2 and containing a dose of 0.64 mg of tetraene. In vitro skin permeation studies in Franz-type diusion chambers resulted in a tetraene flux of (103 10) ng cm2 h1 with a very good linearity (r = 0.99). The relatively low lag time of just 13 min indicates low binding and the accumulation of tetraene in the skin. Finally, the patch was administered to six healthy volunteers, and the pharmacokinetic analysis was performed by nonlinear mixed eects modelling with soft gel oral capsules serving as the reference formulation. The in vivo results correlated well with the in vitro permeation and indicated an initial burst tetraene absorption from the patch that was in parallel with the zero-order kinetics of absorption. The rate of the latter process was in good agreement with the one estimated in vitro. The tetraene absorption rate was therefore slow and prolonged with time, resulting in a bioavailability of 39% relative to the soft gel capsules and a very flat plasma concentration profile

Supercritical CO 2 extraction of eruca sativa using cosolvents: Phytochemical composition by LC-MS analysis

Background: Eruca sativa Mill. is a good source of glucosinolates (GLS), phenolic compounds and unsaturated fatty acids, being a valuable material for the production of functional-foods or nutraceutical ingredients. Extraction by supercritical CO2 (SCO2) can be used and the limitations due to the apolar nature of CO2 can be overcome using co-solvents. In this paper different cosolvents and conditions were used for SCO2 extraction and the composition of the obtained extracts was studied by LC-MS. Results: Water resulted the ideal co-solvent, allowing the extraction of glucosinolates in comparable amounts to the classical procedure with boiling water, as it can be carried out at mild temperatures (45 &#176;C vs. &gt;100 &#176;C). Increasing the pressure improved the GLS extraction. On the other hand polyphenol extraction under the studied conditions was not influenced by pressure and temperature variations. The in vitro antioxidant effect of the obtained extracts was also measured, showing significant activity in the DPPH and FC tests. Conclusions: The GLS, flavonoids and lipids composition of the obtained extracts was studied, showing the presence of numerous antioxidant constituents useful for nutraceutical applications. The extraction method using SCO2 and water as co-solvent presents advantages in terms of safety because these solvents are generally recognised as safe. Water as cosolvent at 8% resulted useful for the extraction of both glucosinolates and phenolics in good amount and is environmentally acceptable as well as safe for food production