A dried blood spot assay with HPLC–MS/MS for the determination of larotrectinib in mouse blood and its application to a pharmacokinetic study

Larotrectinib is a first-generation tropomyosin kinase inhibitor, approved for the treatment of solid tumors. In this paper, we present a validated dried blood spot (DBS) method for the quantitation of larotrectinib from mouse blood using HPLC–MS/MS, which was operated under multiple reaction monitoring mode. To the DBS disc cards, acidified methanol enriched with internal standard (IS; enasidenib) was added and extracted using tert-butyl methyl ether as an extraction solvent with sonication. Chromatographic separation of larotrectinib and the IS was achieved on an Atlantis dC₁₈ column using 10 mm ammonium formate–acetonitrile (30:70, v/v) delivered at a flow-rate of 0.80 ml/min. Under these optimized conditions, the retention times of larotrectinib and the IS were ~0.93 and 1.37 min, respectively. The total run time was 2.50 min. Larotrectinib and the IS were analyzed using positive ion scan mode and parent–daughter mass to charge ion (m/z) transitions of 429.1 → 342.1 and 474.1 → 267.1, respectively, were used for the quantitation. The calibration range was 1.06–5,080 ng/ml. No matrix effect or carryover was observed. Hematocrit did not influence DBS larotrectinib concentrations. All of the validation parameters met the acceptance criteria. The applicability of the validated method was shown in a mouse pharmacokinetic study.     

T1Effects in Sequential Dynamic Susceptibility Contrast Experiments

Residual effects of an initial bolus of gadolinium contrast agent have been previously demonstrated in sequential dynamic susceptibility contrast MR experiments. While these residual effects quickly reach a saturation steady state, their etiology is uncertain, and they can lead to spurious estimates of hemodynamic parameters in activation experiments. The possible influence ofT₁effects is now investigated with experiments in whichT₁weighting is varied as well as with serial regionalT₁measurements. Little evidence for significant residualT₁effects is found, suggesting instead that susceptibility effects underlie these observations. An initial saturation dose of contrast agent minimizes this effect.     

Optical Glucose Monitoring Based on Femtosecond Two-Color Pulse Interferometry

We demonstrate the potential of femtosecond two-color pulse interferometry for in vitro optical glucose monitoring, by dispersion of the group refractive index in a glucose solution sample with respect to a red-color light and a blue-color light. By comparison with femtosecond one-color pulse interferometry, the basic performance of the present system with regard to sensitivity, quantitativeness, and tolerance to surrounding disturbances, is evaluated. The resulting accuracy and precision of glucose determination are 77 and 118mg/dl for 10-mm-sample-thickness, respectively. This near-common-path configuration of the two-color pulse light provides good stability to fluctuations of sample temperature, which is important in clinical applications. Considering the performance of femtosecond two-color pulse interferometry as an optical glucose sensor, a suitable measurement site for in vivo optical glucose monitoring is discussed.     

Endoscopic Observation of Tissue by Narrowband Illumination

We propose a new illumination method for a medical endoscope: narrow band imaging (NBI), in which the spectral bandwidth of the filtered light is narrowed. To confirm how the spectral specifications of the filtered light influence a reproduced image, an experiment was conducted observing the endoscopic images of the back mucosa of a human tongue. In addition, the effect of NBI on endoscopic images was investigated through preliminary clinical tests in colonoscopy and upper gastrointestinal endoscopy. It has been shown that NBI can enhance the capillary pattern and the crypt pattern on the mucosa. These patterns are useful features for diagnosing an early cancer.     

Succinic acid adsorption from fermentation broth and regeneration

More than 25 sorbents were tested for uptake of succinic acid from aqueous solutions. The best resins were then tested for successive loading and regeneration using hotwater. The key desired properties for an ideal sorbent are high capacity, complete stable regenerability, and specificity for the product. The best resins have a stable capacity of about 0.06 g of succinic acid/g of resin at moderate concentrations (1–5 g/L) of succinic acid. Several sorbents were tested more exhaustively for uptake of succinic acid and for successive loading and regeneration using hot water. One resin, XUS 40285, has a good stable isotherm capacity, prefers succinate over glucose, and has good capacities at both acidic and neutral pH. Succinic acid was removed from simulated media containing salts, succinic acid, acetic acid, and sugar using a packed column of sorbent resin, XUS 40285. The fermentation byproduct, acetate, was completely separated from succinate. A simple hot water regeneration successfully concentrated succinate from 10 g/L (inlet) to 40–110 g/L in the effluent. If successful, this would lower separation costs by reducing the need for chemicals for the initial purification step. Despie promising initial results of good capacity (0.06 g of succinic/g of sorbent), 70% recovery using hot water, and a recovered concentration of >100 g/L, this regeneration was not stable over 10 cycles in the column. Alternative regeneration schemes using acid and base were examined. Two (XUS 40285 and XFS-40422) showed both good stable capacities for succinic acid over 10 cycles and >95% recovery in a batch operation using a modified extraction procedure combining acid and hot water washes. These resins showed comparable results with actual broth.     

原子吸收法测定血清中的无机磷和钙

本文叙述了用原子吸收法测定同一个少量血清样品中的无机磷和钙。血清用高氨酸沉淀蛋白后,加过量钼酸铵。在pH0.4～1.6范围内,用乙酸丁酯萃取生成的微量磷钼酸,与过量的钼酸铵分离。水相测钙,有机相用稀氨水反萃后测钼,间接分析磷。     

添加有机肥和葡萄糖对铜毒害旱地红壤微生物生物量的影响

在预培红壤中加入定量的有机肥和葡萄糖及不同浓度的Cu,25℃培养14d，测定了土壤微生物生物量C（Cmic),N(Nmic)。结果表明，存在有机肥和葡萄糖时，土壤中Cmic和Nmic随着Cu浓度的增加而降低；Cmic/Nmic随着Cu浓度的增加而增大。施加有机肥和葡萄糖的土壤中，在所有Cu处理浓度下，土壤中Cmic和Nmic均比未加有机物质处理高，特别是有机肥处理中土壤Cmic和Nmic均比其它处理高得多，说明有机肥可明显减轻Cu对土壤微生物生物量的毒性，同时也说明有机肥可提供微生物N源。不含Cu时，加入有机肥和葡萄糖导致土壤中Cmic和Nmic增加，其中有机肥明显。     

降铅冲剂对低水平铅暴露仔鼠血铅及脑铅的影响

目的:研究降铅冲剂对低水平铅暴露仔鼠血铅及脑铅的影响,为评价降铅冲剂的作用提供依据。方法:选用Wister大鼠仔鼠60只,体质量80~100 g,随机分成6组,每组10只,分别为空白组、模型对照组、EDTA对照组、降铅冲剂低剂量组、降铅冲剂中剂量组、降铅冲剂高剂量组;造模后开始给药,EDTA对照组给CaNa2EDTA注射液10(mg/kg)/d腹腔注射,降铅冲剂低、中、高剂量组分别予降铅冲剂5(g/kg)/d、10(g/kg)/d、20(g/kg)/d的剂量灌胃,空白组和模型对照组予等量蒸馏水灌胃,给药共30 d。用石墨炉原子吸收光谱仪测定仔鼠血铅、脑铅。结果:(1)染铅后,各染铅组的血铅水平与空白组比较都显著升高(P<0.001),经过30 d的治疗后,各治疗组的治疗后血铅水平均有不同程度下降,与模型对照组比较均有统计学意义。(2)染铅后,各染铅组的脑铅水平与空白组比较都显著升高(P<0.05),治疗后,各组脑铅与治疗前比较均显著升高,降铅冲剂低、中剂量组的脑铅与模型对照组比较显著下降。结论:降铅冲剂能显著降低低水平铅暴露仔鼠的血铅和脑铅含量,其综合疗效优于CaNa2EDTA。     

Effects of sugar inhibition on cellulases and β-glucosidase during enzymatic hydrolysis of softwood substrates

A quantitative approach was taken to determine the inhibition effects of glucose and other sugar monomers during cellulase and β-Glucosidase hydrolysis of two types of cellulosic material: Avicel and acetic acid-pretreated softwood. The increased glucose content in the hydrolysate resulted in a dramatic increase in the degrees of inhibition on both β-Glucosidase and cellulase activities. Supplementation of mannose, xylose, and galactose during cellobiose hydrolysis did not show any inhibitory effects on β-Glucosidase activity. However, these sugars were shown to have significant inhibitory effects on cellulase activity during cellulose hydrolysis. Our study suggests that high-substrate consistency hydrolysis with supplementation of hemicellulose is likely to be a practical solution to minimizing end-product inhibition effects while producing hydrolysate with high glucose concentration.