Skin targeting of resveratrol utilizing solid lipid nanoparticle-engrossed gel for chemically induced irritant contact dermatitis

Abstract

Irritant contact dermatitis (ICD) is a chronic and relapsing skin disease with severe eczematous lesions. Despite its growing prevalence, therapeutic treatments remain limited. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation, and increase in transepidermal water loss. An innovative dermal treatment is essential to reduce the side effects of corticosteroids. Topical resveratrol (RES), although effective for ICD, is a challenging molecule due to low solubility and poor bioavailability. The objective of this work was to build RES-loaded solid lipid nanoparticles (RES-SLNs) with skin targeting. For this purpose, RES-SLNs were prepared using the probe ultrasonication method utilizing Precirol ATO 5 and Tween 20. The RES-SLNs were evaluated for particle size, entrapment efficiency (EE), and transmission electron microscopy (TEM) studies. Further, RES-SLNs were incorporated into Carbopol gel and investigated for ex vivo skin permeation, deposition study on human cadaver skin, and finally skin irritation study on New Zealand White rabbits. It was further assessed for possible beneficial effects on ICD using BALB/c mice. RES-SLN showed mean size below 100 nm and 68–89% EE. TEM studies confirmed spherical particles in the nanometer range. An ex vivo study of RES-SLN-loaded gel exhibited controlled drug release up to 24 h; similarly, in vitro drug deposition studies showed potential of skin targeting with no skin irritation. RES-SLN gel confirmed competent suppression of ear swelling and reduction in skin water content in the BALB/c mouse model of ICD when compared to marketed gel. Thus, the formulated RES-SLN gel would be a safe and effective alternative to conventional vehicles for treatment of ICD.

http://ift.tt/2gIBwI5

Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity?

Abstract

Signalling pathways involving protein kinase, insulin-like growth factor 1, insulin receptors and the phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) system are critical in promoting oncogenesis. The use of anticancer agents that inhibit these pathways frequently results in hyperglycaemia, an on-target effect of these drugs. Hyperglycaemia induced by these agents denotes optimal inhibition of the desired pharmacological target. As hyperglycaemia can be treated successfully and effectively with metformin, managing this complication by reducing the dose of or discontinuing the anticancer drug may be counterproductive, especially if it is otherwise effective and clinically tolerated. The use of metformin to treat hyperglycaemia induced by anticancer drugs provides a valuable therapeutic opportunity of potentiating their clinical anticancer effects. Although evidence from randomised controlled trials is awaited, extensive preclinical evidence and clinical observational studies suggest that metformin has anticancer properties that improve overall survival in patients with diabetes and a variety of cancers. Metformin has also been reported to reverse resistance to epidermal growth factor receptor (EGFR)-inhibiting tyrosine kinase inhibitors. This review summarises briefly the role of the above signalling pathways in oncogenesis, the causal association between inhibition of these pathways and hyperglycaemia, and the effect of metformin on clinical outcomes resulting from its anticancer properties. The evidence reviewed herein, albeit almost exclusively from observational studies, provides support for a greater use of metformin not only in patients with cancer and diabetes or drug-induced hyperglycaemia but also potentially as an anticancer drug. However, prospective randomised controlled studies are needed in all these settings to better assess the effect on clinical outcomes of adding metformin to ongoing anticancer therapy.

http://ift.tt/2gSmOl9

Facile synthesis of uniform hierarchical composites CuO-CeO 2 for enhanced dye removal

Abstract

The hierarchically shaped CuO-CeO₂ composites were prepared through a facile solvothermal method without using any template. The as-prepared products were characterized by X-ray powder diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, and N₂ adsorption–desorption analysis. In the characterization, we found that CuO-CeO₂ composites were showed uniform size and morphology which were consisted of the secondary nanoflakes interconnected with each other. Most interestingly, the composites showed efficient performance to remove methyl blue and Congo red dyes from water with maximum adsorption capacities of 2131.24 and 1072.09 mg g⁻¹, respectively. In addition, because of their larger surface area and the unique hierarchical structures, the adsorption performance of the CuO-CeO₂ composites is much better than the materials of CuO and CeO₂.

http://ift.tt/2hVuFMp

New self-assembled material based on Ru nanoparticles and 4-sulfocalix[4]arene as an efficient and recyclable catalyst for reduction of brilliant yellow azo dye in water: a new model catalytic reaction

Abstract

New self-assembled material (Ru@SC) with ruthenium nanoparticles (Ru NPs) and 4-sulfocalix[4]arene (SC) is synthesized in water at room temperature. Ru@SC is characterized by thermal gravimetric analysis, FT-IR, powder x-ray diffraction, TEM and SEM analysis. The size of Ru nanoparticles in the self-assembly is approximately 5 nm. The self-assembled material Ru@SC shows an efficient catalytic reduction of toxic 'brilliant yellow' (BY) azo dye. The reduced amine products were successfully separated and confirmed by single-crystal XRD, NMR and UV-Vis spectroscopy. Ru@SC showed a better catalytic activity in comparison with commercial catalysts Ru/C (ruthenium on charcoal 5 %) and Pd/C (palladium on charcoal 5 and 10 %). The catalyst also showed a promising recyclability and heterogeneous nature as a catalyst for reduction of 'BY' azo dye.

Graphical abstract

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The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers

Abstract

Purpose

Piperine (PIP) has been found to inhibit P-glycoprotein (P-gp) function in rats, suggesting that it may have the potential to modulate P-gp-mediated drug efflux in humans. The aim of this study was to evaluate the effect of PIP on the pharmacokinetics of fexofenadine (FEX), a P-gp substrate, in healthy volunteers.

Methods

An open-label, two-period, sequential study involving 12 healthy volunteers was conducted. A single oral dose of FEX 120 mg was given to volunteers during the control phase and after the treatment phase. A once-daily oral dose of PIP 20 mg was given to volunteers during the treatment phase (10 days). Blood samples were collected at predefined time intervals, and plasma samples containing FEX were analyzed by liquid chromatography-tandem mass spectrometry.

Results

Treatment with PIP significantly increased maximum plasma concentration of FEX [406.9 (control) vs. 767 ng/mL (treatment)] and area under the plasma concentration–time curve [3403.7 (control) vs. 5724.7 ng.h/mL (treatment)] when compared to the control phase. In contrast, PIP treatment significantly decreased apparent oral clearance of FEX [35.4 (control) vs. 20.7 L/h (treatment)] as compared to the control. There was no significant change observed in the half life and renal clearance of FEX between the treatment phase and control phase.

Conclusions

The results suggest that altered pharmacokinetics and enhanced bioavailability of FEX might be attributed to PIP-mediated inhibition of P-gp drug efflux. Therefore, intake of PIP or dietary supplements containing PIP may potentially enhance the absorption or bioavailability of P-gp substrate drugs in addition to FEX.

http://ift.tt/2hEDACu

Female Reproductive Parameters in Wild Geladas ( Theropithecus gelada )

Abstract

Accurate data on reproductive parameters are essential for evaluating the adaptive and mechanistic bases of variation within and between species. Here, we combine fecal ovarian hormone analysis with measurements of sex skin swellings and reproductive behavior to describe female reproduction in geladas living in the Simien Mountains National Park, Ethiopia. We collected 10 years of reproductive data from 197 females across 36 units, with hormone data from a subset of these females (60 females from 16 units). First, we use these data to calculate age at maturation, age at first birth, interbirth interval, menstrual cycle length, gestation length, and duration of postpartum amenorrhea. Second, we present composite profiles of ovarian hormones, i.e., estrogens, progestogens, and sex skin measures across reproductive stages. Third, we examine whether ovarian hormones, sex skin phenotypes, and/or reproductive behaviors reliably reflect fertility or pregnancy in female geladas. The reproductive parameters calculated from our data were similar to those in previous studies on geladas and within the range of those for closely-related baboon species. We were able to reliably identify fertility and pregnancy using fecal estrogens only. The tumescent sex skin phenotypes and reproductive behaviors associated with fertility were also observed across all reproductive stages. We suggest that their presence outside of fertility may be a by-product of the flexibility needed for one or more female counterstrategies to infanticide.

http://ift.tt/2hJj6Mk

Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus

Abstract

Introduction

Sodium glucose co-transporter 2 (SGLT2) inhibitors exhibit diuretic activity, which is a possible mechanism underlying the cardiovascular benefit of these inhibitors. However, the osmotic diuresis-induced increase in urine volume, and the risk of dehydration have been of concern with SGLT2 inhibitor treatment. This study aimed to investigate the mechanism underlying SGLT2 inhibitor canagliflozin-induced diuresis in Japanese type 2 diabetes mellitus (T2DM) patients.

Methods

Thirteen T2DM patients received a daily oral dose of 100 mg canagliflozin before breakfast for 6 days. Blood and urine samples were collected at predetermined time points. The primary endpoint was evaluation of correlations between changes from baseline in urine volume and factors that are known to affect urine volume and between actual urine volume and these factors.

Results

Canagliflozin transiently increased urine volume and urinary sodium excretion on Day 1 with a return to baseline levels thereafter. Canagliflozin administration increased urinary glucose excretion, which was sustained during repeated-dose administration. Plasma atrial natriuretic peptide (ANP) and N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels decreased, while plasma renin activity increased. On Day 1 of treatment, changes in sodium and potassium excretion were closely correlated with changes in urine output. A post hoc multiple regression analysis showed changes in sodium excretion and water intake as factors that affected urine volume change at Day 1. Furthermore, relative to that at baseline, canagliflozin decreased blood glucose throughout the day and increased plasma total GLP-1 after breakfast.

Conclusion

Canagliflozin induced transient sodium excretion and did not induce water intake at Day 1; hence, natriuresis rather than glucose-induced osmotic diuresis may be a major factor involved in the canagliflozin-induced transient increase in urine output. In addition, canagliflozin decreased plasma ANP and NT-proBNP levels and increased plasma renin activity, which may be a compensatory mechanism for sodium retention, leading to subsequent urine output recovery.

Clinical trial registration

UMIN000019462.

Funding

Mitsubishi Tanabe Pharma Corporation.

http://ift.tt/2hpZ2xy