An Artificial Gut/Absorption Simulator: Simultaneous Evaluation of Desupersaturation and Absorption from Ketoconazole Supersaturated Solutions

For supersaturating formulations of BCS-II compounds, which by definition have high intestinal permeability, a closed USP apparatus does not provide the necessary absorptive conditions during dissolution. To address this, an artificial gut simulator (AGS) has been constructed consisting of a 2.5 mL donor compartment in which a hollow fiber-based absorption module is suspended. Drug from donor diffuses across the hollow fiber membrane to be absorbed by the continuously flowing intraluminal receiver fluid. The membrane surface area and intraluminal fluid flow rate are tuned to obtain the physiologically observed absorption rate constant for a weakly basic, poorly water-soluble model compound, ketoconazole (KTZ). Supersaturated solutions of KTZ were generated in the donor in pH 6.5 phosphate buffer by the pH-shift method in the absence (closed system, control) and presence (open system, biorelevant) of an optimally or suboptimally tuned absorption module. Drug concentrations in the donor and intraluminal fluids were determined by in-line UV spectroscopy. The presence of an absorptive sink reduced the supersaturated solution's crystallization propensity, more so in the case of the optimally tuned AGS. This study demonstrates the significance of simulating absorption of drug at a physiological rate during dissolution studies, especially to predict the performance of formulations of BCS-II drugs.     

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.     

Protective effect of platycodin D on liver injury in alloxan-induced diabetic mice via regulation of Treg/Th17 balance

Platycodin D is a major pharmacological constituent of Platycodi Radix with immunomodulatory activity. The present study was designed to investigate how platycodin D (PLD) reveals liver injury in diabetic mice and its mechanism. Fifty mice were divided into five groups randomly: control group, model group, rosiglitazone (ROG, 10 mg/kg) group, PLD (50 mg/kg) group, and PLD (100 mg/kg) group. Diabetes was induced with the injection of alloxan monohydrate (150 mg/kg) subcutaneously, and animals with blood glucose level of ≥ 250 mg/dl were considered as diabetic mice. After the first day of diabetes induction, the treatments were performed for 8 weeks. Then the animals were anaesthetized, and blood and liver samples were also collected for further assay. PLD significantly decreased the serum levels of glucose, insulin, interleukin-6 (IL-6), interleukin-1β, tumor necrosis factor-α (TNF-α), and interleukin (IL)-17A and increased IL-10 level in serum. PLD effectively downregulated aspartate transaminase (AST), alanine aminotransferase (ALT), total cholesterol (TC), and triglycerides (TG) in liver. PLD also attenuated liver histological change. In addition, PLD significantly attenuated IL-17A and IL-10 levels in vitro, flow cytometry (FCM) studies also showed that PLD remarkably inhibited Th17 cells and significantly increased Treg cells in liver tissues and spleen cells. Western blot demonstrated PLD inhibited the phosphorylation of JAK and STAT-3 and the expression of RORγt and increased the expression of Foxp3. The findings showed that PLD exerts beneficial effects on alloxan-induced liver injury in mice.     

A combination of Sinomenine and Methotrexate reduces joint damage of collagen induced arthritis in rats by modulating osteoclast-related cytokines

ObjectiveTo analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines.MethodsCIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR.ResultsSIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS.ConclusionSIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.     

Differential scanning calorimetry of blood plasma for clinical diagnosis and monitoring

Differential scanning calorimetry (DSC) provides a useful method to study the unfractionated plasma proteome. Plasma from healthy individuals yields a reproducible signature thermogram which results from the weighted sum of the thermal denaturation of the most abundant plasma proteins. Further investigation of the thermogram for healthy individuals showed it to be sensitive to ethnicity and gender. DSC analysis of plasma from diseased individuals revealed significant changes in the thermogram which are suggested to result not from changes in the concentration of the major plasma proteins but from interactions of small molecules or peptides with these proteins. Closer examination of the diseased thermograms showed a thermogram characteristic of each disease. For cervical cancer, the DSC method yields a progressively shifted thermogram as the disease advances from pre-invasive conditions to late stage cancer. Our application of the DSC method has provided a potential tool for the early diagnosis, monitoring and screening of cancer patients.     

Healthcare providers' role regarding the safe and appropriate use of herbal products by breastfeeding mothers: A systematic literature review

BackgroundBreastfeeding women often use herbal products to increase their milk supply. The aim of this study was to summarize the literature about the role of healthcare providers in advising breastfeeding women about herbal product use.MethodsPubmed, ScienceDirect, Web of Science, and CINAHL databases were searched for articles written in English using the Keywords: “breastfeeding” or “lactation” and “herbal medicine*“, “botanical*“, “dietary supplement*“, “natural product*“, “traditional medicine*” or “complementary medicine*“.ResultsTwenty-two articles were included in this review. A lack of inter-professional communication and guidelines, a lack of provider confidence and knowledge about the evidence for the efficacy and safety of herbal products were identified as causing a ‘gap’ between current practice and expectations of breastfeeding women seeking advice about their use herbal products.ConclusionsStrategic and collaborative efforts between key stakeholders are required to ensure the needs of women who are considering herbal product use while breastfeeding are met.     

Metam sodium exposure during pregnancy and lactation in mice caused behavioral abnormalities and oxidative stress in offspring

Metam sodium (MS) is a widespread biocide with a broad-spectrum activity. Here, we addressed the behavioral impact of MS by exposing female mice to 50, 100 and 150 mg/kg of MS during both pregnancy and lactation, and evaluated the oxidative stress as a potential mechanism of MS-induced neurotoxicity. The results showed that MS affected fertility and reproduction parameters as well as some aspects of maternal behavior, especially at high doses. In offspring, MS caused a significant delay in the ontogeny of sensorimotor functions. In addition, treated mice exhibited during adulthood an increase of anxiety-like, depression-like behaviors as well as learning and memory impairment. These alterations were accompanied by an increase of the superoxide dismutase activity, and a significant decreased catalase and malondialdehyde activities in specific brain areas. The present work revealed that early exposure to MS induced sensorimotor and behavioral impairments in offspring likely associated with onset of oxidative stress.