lignans and aschantin

Study of mixing and segregation of granular materials was performed in a Bohle bin blender using both computational modeling and experiments. A multicomponent mixture of pharmaceutical excipients and coated theophylline granules, an active pharmaceutical ingredient (API) was considered as the blend formulation. A DEM (Discrete Element Method) Model was developed to simulate the flow and mixing of the multicomponent blend to compare with the experimental data. DEM is a numerical modeling technique which incorporates all the material properties (such as Particle size, density, elastic modulus, yield strength, Poisson's ratio, work function etc.)to simulate granular flow (such as mixing, conveying) of particles. In simulation, the degree (Relative standard deviation) of mixing in a Bohle bin blender was assessed as a function of critical processing parameters (loading pattern, rotational rate, and fill percentage). Numerical simulation results reveal radial mixing in a Bohle bin blender is faster than axial mixing due to symmetric geometry limitation. This study investigates a numerical model-based approach to study the effect of the critical process parameters on the mixing dynamics in Bohle bin blender for a moderately cohesive pharmaceutical formulation. The DEM model can be used to provide crucial insights to developed optimized mixing protocols to ascertain the best mixing conditions for different formulation. As for example, as we try to develop a mixing protocol for another formulation with different operational parameters such as loading pattern, rotational speed, and fill percentage, one can device an optimized mixing protocol of the formulation with the help of this DEM model.

Topics: Benzodioxoles; Chemistry, Pharmaceutical; Computer Simulation; Excipients; Lignans; Particle Size; Pharmaceutical Preparations; Theophylline

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Topics: Benzodioxoles; Lignans; Models, Statistical; Pharmaceutical Preparations; Principal Component Analysis; Solubility; Tablets

Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca(2+)-antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin-enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4'-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4'-hydroxylation, and CYP3A4-mediated midazolam 1'-hydroxylation, with Ki values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1'-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.

Topics: Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Glucuronosyltransferase; Humans; Lignans; Microsomes, Liver; Time Factors

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, forms two different complexes, complex 1 and 2, and plays a key role in the regulation of Akt signaling-mediated cell proliferation and transformation. This study reveals aschantin, a natural compound abundantly found in Magnolia flos, as a novel mTOR kinase inhibitor. Aschantin directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not PI3K and PDK1. Aschantin inhibited epidermal growth factor (EGF)-induced full activation of Akt by phosphorylation at Ser473/Thr308, resulting in inhibition of the mTORC2/Akt and Akt/mTORC1/p70S6K signaling pathways and activation of GSK3β by abrogation of Akt-mediated GSK3β phosphorylation at Ser9. The activated GSK3β inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through the ubiquitination-mediated proteasomal degradation pathway. Notably, aschantin treatment decreased c-Jun stability through inhibition of the mTORC2-Akt signaling pathway, which suppressed EGF-induced anchorage-independent cell transformation in non-malignant JB6 Cl41 and HaCaT cells and colony growth of LNCaP and MIAPaCa-2 cancer cells in soft agar. Altogether, the results show that aschantin targets mTOR kinase and destabilizes c-Jun, which implicate aschantin as a potential chemopreventive or therapeutic agent.

Topics: Animals; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lignans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Multiprotein Complexes; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Activated microglia produces diverse neurotoxic factors such as nitric oxide (NO) and tumor necrosis factor-alpha that serve as apoptotic inducers resulting in various neurodegenerative diseases. The inhibition of microglia-derived NO production by inducible nitric oxide synthase (iNOS) has been reported to be beneficial in retarding neurodegenerative disorders. Three active lignans have been isolated from the flower buds of Magnolia fargesii by the bioassay-guided fractionation using lipopolysaccharide (LPS)-activated BV-2 microglial cell culture system. The structures of them were identified as kobusin (1), aschantin (2) and fargesin (3) by the analyses of spectroscopic data. They inhibited the production of NO by activated microglia. Their IC(50) values were 21.8 +/- 3.7, 14.8 +/- 2.5 and 10.4 +/- 2.8 microg/mL, respectively. They suppressed LPS-induced NF-kappaB activation and the expression of iNOS protein and mRNA. Furthermore, they showed scavenging activity of neurotoxic peroxynitrite that can be produced by NO and superoxide anion. These results imply that lignans from Magnolia fargesii might be beneficial for the treatment of neuro-inflammatory diseases through the inhibition of iNOS expression and peroxynitrite scavenging potential.

Topics: Animals; Benzodioxoles; Cell Line; Enzyme Inhibitors; Flowers; Free Radical Scavengers; Inhibitory Concentration 50; Lignans; Magnolia; Mice; Microglia; Molecular Structure; Nitric Oxide; Nitric Oxide Synthase Type II