药用辅料对CYP3A活性的影响及其对仿制药质量和疗效一致性评价的指导作用

药物制剂的处方和工艺是保证药物质量和疗效的基础，药用辅料是药物制剂处方的重要组成部分。部分药用辅料可影响CYP3A的活性，继而可能影响其底物在体内的代谢和生物利用度。在中国和美国，相对生物利用度是仿制药研究的关键内容。我国正在推进仿制药质量和疗效一致性评价。因此，了解药用辅料对CYP3A的影响及其对一致性评价的指导作用具有十分重要的现实意义。     

Carbon Chain Length Modulates MDA-MB-231 Breast Cancer Cell Killing Mechanisms by Mitochondrially Targeted Aryl−Urea Fatty Acids

Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl−urea fatty acid ( 1 g ; 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA-MB-231 breast cancer cell viability. To optimize the aryl−ureas the present study evaluated mitochondrial targeting by 1 g analogues containing alkyl chains between 10–17 carbons. Using the dye JC-1, the C12−C17 analogues efficiently disrupted the mitochondrial membrane potential (IC₅₀s 3.5±1.2 to 7.6±1.1 μM) and impaired ATP production; shorter analogues were less active. 7-Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7-aminoactinomycin D/annexin V staining ratios 4.3–6.0). Indeed, 1 g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl−ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion.     

Annealing and doping-dependent magnetoresistance in single layer poly(3-hexyl-thiophene) organic semiconductor device

We compare the current density–voltage (J–V) and magnetoconductance (MC) response of a poly(3-hexyl-thiophene) (P3HT) device (Au/P3HT(350 nm)/Al) before and after annealing above the glass transition temperature of 150 °C under vacuum. There is a decrease of more than 3 orders of magnitude in current density due to an increase of the charge injection barriers after de-doping through annealing. An increase, approaching 1 order of magnitude, in the negative MC response after annealing can be explained by a shift in the Fermi level due to de-doping, according to the bipolaron mechanism. We successfully tune the charge injection barrier through re-doping by photo-oxidation. This leads to the charge injection and transport transitioning from unipolar to ambipolar, as the bias increases, and we model the MC response using a combination of bipolaron and triplet-polaron interaction mechanisms.     

Nutrient digestibility and endogenous protein losses in the foregut and small intestine of weaned dairy calves fed calf starters with conventional or enzyme-treated soybean meal

The aims of this experiment were (1) to compare the effects of a soybean meal with an enzymatic treatment (ESBM) to reduce the concentration of antinutritional factors versus a standard soybean meal (SBM) on foregut and small intestine digestion in weaned dairy calves and (2) to estimate the endogenous losses of crude protein (CP) in the small intestine. Our hypothesis was that a diet containing ESBM instead of SBM would improve ruminal and small intestine digestion and absorption of nutrients. A T-cannula was placed in the duodenum, and a second T-cannula was installed in the distal ileum of 12 Holstein calves at approximately 3 wk of age. Calves were weaned on d 42, and on d 50 they were assigned randomly to a quadruplicated 3 × 3 Latin square with 10-d periods. Digesta samples were collected on d 7 and 8 from the ileum and d 9 and 10 from the duodenum. The diets were fed for ad libitum intake and consisted of a calf starter (CS) of 20% CP with SBM as the main source of protein (CTRL), and an isonitrogenous CS with an ESBM instead of SBM (ENZT). A third diet with a low content of CP (10%) and no soy protein was fed to estimate endogenous N losses and digestibilities of test ingredients. Flows and digestibilities of nutrients were compared between CTRL and ENZT and their test ingredients (SBM vs. ESBM, respectively). Duodenal net flows of CP and total AA as well as ruminal microbial protein synthesis per kilogram of digested CP were greater, and flow of nonprotein N and CP true (corrected by endogenous and microbial flows) foregut digestibility were lower with ENZT than CTRL. The apparent small intestine digestibilities of CP and total AA were greater for ESBM than SBM, but there were no differences between the CTRL and ENZT diets. We observed no differences in digestibilities at the duodenum or ileum of starch or NDF, but true small intestine digestibilities of CP and all AA were greater with ENZT than CTRL. Total endogenous protein losses in the small intestine estimated from calves fed the low-CP with no soy protein diet were 37 ± 1.5 g of CP and 29 ± 1.4 g of AA/kg of DMI. These values may be considered the basal endogenous losses as they are similar to values obtained with the regression method, which estimates N losses when dietary N is null. Our results indicated that the inclusion of an ESBM improved the efficiency of ruminal microbial protein synthesis per digested kilogram of organic matter and CP, and increased CP and AA absorption in the small intestine despite a greater proportion of undigested dietary protein entering the duodenum.     

Simultaneous accommodation of Dy3+ at the lattice site of β-Ca3(PO4)2 and t-ZrO2 mixtures: Structural stability,mechanical, optical,and magnetic features

Structurally stable β-Ca₃(PO₄)₂/t-ZrO₂ composite mixtures with the aid of Dy³⁺ stabilizer were accomplished at 1500°C. The precursors comprising Ca²⁺, P⁵⁺, Zr⁴⁺, and Dy³⁺ have been varied to obtain five different combinations. The results revealed the fact that complete phase transformation of calcium-deficient apatite to β-Ca₃(PO₄)₂ occurred only at 1300°C, whereas the evidence of t-ZrO₂ crystallization is obvious at 900°C. The dual occupancy of Dy³⁺ at β-Ca₃(PO₄)₂ and t-ZrO₂ structures was evident; however, Dy³⁺ initially prefers to occupy β-Ca₃(PO₄)₂ lattice until its saturation limit and thereafter accommodates at the lattice site of ZrO₂. The typical absorption and emission behavior of Dy³⁺ were noticed in all the systems and, moreover, the surrounding symmetry of Dy³⁺ domains has been determined from the luminescence study. All the systems ensured paramagnetic response that is generally contributed by the presence of Dy³⁺. A gradual increment in the phase content of t-ZrO₂ in the composite mixtures ensured a significant improvement in the hardness and Young's modulus of the investigated compositions.     

Formulation and in vitro Evaluation of pH-Sensitive Cross-linked Xanthan Gum-Grafted Acrylic Acid Copolymer for Controlled Delivery of Perindopril Erbumine (PE)

A novel xanthan gum-co-acrylic acid superabsorbent hydrogel composite was formulated by free radical polymerization reaction of acrylic acid on xanthan gum. Effect of variables like dynamic swelling ratio, equilibrium swelling ratio, drug loading and drug release was investigated. Swelling ratio increases with decrease in crosslinker concentration. Drug release studies were conducted in pH 7.4 and 0.1N HCl. In acidic environment, drug release was low whereas it was sustained release in alkaline. XG4 showed significant swelling and drug release up to 24?hr. Physicochemical evaluation also confirmed it was optimized formulation. Hence XG4-co-AA was optimized for once daily dose of Perindopril Erbumine.     

Macrophage Immunomodulation Through New Polymers that Recapitulate Functional Effects of Itaconate as a Power House of Innate Immunity

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. A library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior is developed. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers result in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibits bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrate a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.