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.     

A review of computational modeling and deep brain stimulation: applications to Parkinson's disease

Biophysical computational models are complementary to experiments and theories, providing powerful tools for the study of neurological diseases. The focus of this review is the dynamic modeling and control strategies of Parkinson's disease (PD). In previous studies, the development of parkinsonian network dynamics modeling has made great progress. Modeling mainly focuses on the cortex-thalamus-basal ganglia (CTBG) circuit and its sub-circuits, which helps to explore the dynamic behavior of the parkinsonian network, such as synchronization. Deep brain stimulation (DBS) is an effective strategy for the treatment of PD. At present, many studies are based on the side effects of the DBS. However, the translation from modeling results to clinical disease mitigation therapy still faces huge challenges. Here, we introduce the progress of DBS improvement. Its specific purpose is to develop novel DBS treatment methods, optimize the treatment effect of DBS for each patient, and focus on the study in closed-loop DBS. Our goal is to review the inspiration and insights gained by combining the system theory with these computational models to analyze neurodynamics and optimize DBS treatment.     

Modifications of He implantation induced cavities in silicon by MeV silicon implantation

Doppler broadening spectroscopy (DBS) coupled to a slow positron beam has been used to investigate the formation of He-cavities in the presence of high vacancy concentrations in Cz-Si (1 1 1). Si samples were first implanted with MeV Si ions in order to create a damaged Si layer. DBS measurements show the presence of divacancy (SV₂/SSi lattice=1.052,WV₂/WSi lattice=0.83) from the surface up to 4.2 μm depth with a concentration higher than 10¹⁸ cm⁻³. The thickness of this damaged layer was confirmed by spreading resistance measurements. In the second step, samples were implanted with 50 keV ³He with fluence of 10¹⁶ cm⁻². DBS results show that the apparent divancancy concentration decreases at ³He implantation depth ∼435 nm due to ³He passivation of vacancies that occurs during the implantation process. After 900 °C annealing, large defects are detected at depth up to 2 μm and (S, W) values suggest the detection of cavities at the implantation depth. We also report the possible presence of impurity complexes. The formation of these complexes is attributed to the gettering of metallic impurities present in the Si sample.     

Ir（Ⅳ）—KBrO3—DBS—偶氮氯膦催化分光光度法测定微量铱的研究

ＫＢｒＯ３－ＤＢＳ偶氮氯膦在０．８ｍｌ．Ｌ＾－１的Ｈ２ＳＯ４介质中长时间加热亦无明显褪色现象，但在有微量铱存在时，褪色反应在３ｍｉｎ内完成，且与Ｉｒ（Ⅳ）的浓度有良好的线性关系，据此建立了微量铱的催化褪色分光光度分析法，其检出限为０．０１μｇ．１０ｍＬ＾－１铱的含量在０．０１－０．２０μｇ．１０ｍＬ＾－１范围内符合比尔定律。     

Study on the Nonisothermal Melt Crystallization Kinetics of DBS/PBT Blends

The modified Avrami, Mo, and Kissinger models were applied to investigate the nonisothermal melt crystallization process of dibenzylidene sorbitol (DBS)/poly(butylene terephthalate) (PBT) blends by differential scanning colorimetry (DSC) measurements. The modified Avrami model can describe the nonisothermal melt crystallization processes of DBS/PBT blends fairly well. The cooling rates and the blend composition affect the crystallization of the blends according to Mo crystallization kinetics parameters. The Mo model shows that F(T) increases with increasing crystallinity, indicating that the needed cooling rate when it reached a certain crystallinity increased in unit time, the crystallization rate of DBS/PBT blends is faster than the crystallization rate of pure PBT, and the crystallization rate of the DBS/PBT blends with 0.5% DBS is fastest. The Kissinger model showed that the crystallization activation energy of DBS/PBT blends is lower than the activation energy of pure PBT; the crystallization activation energy of the DBS/PBT blends with 0.5% DBS is the lowest.     

稀土(La3+,Pr3+)-DBS-偶氮胂有色配合物组成和稳定常数的吸收光谱法测定

稀土 (La3 + ,Pr3 + )在酸性条件下与DBS 偶氮胂发生配位反应。首先对光谱数据进行因子分析法处理从而判断出只生成一类配合物 ,进而采用线性回归法计算配合物组成、摩尔吸光系数、表观稳定常数及配位体浓度。实验结果表明 :在 1mol·L-1HCl介质中 ,La3 + 、Pr3 + 与DBS 偶氮胂形成M∶L =1∶3的配合物 ,其摩尔吸光系数分别为 1 399× 10 5和 1 5 17× 10 5L·mol-1·cm-1,表观稳定常数logβ3 分别为 15 36和 15 34。     

Analysis of cocaine and two metabolites in dried blood spots by liquid chromatography with fluorescence detection: a novel test for cocaine and alcohol intake

An original HPLC method coupled to spectrofluorimetric detection is presented for the simultaneous analysis in dried blood spots (DBS) of cocaine and two important metabolites, namely benzoylecgonine (its main metabolite) and cocaethylene (the active metabolite formed in the presence of ethanol). The chromatographic analysis was carried out on a C8 column, using a mobile phase containing phosphate buffer (pH 3.0)-acetonitrile (85:15, v/v). Native analyte fluorescence was monitored at 315 nm while exciting at 230 nm. A fast and feasible sample pre-treatment was implemented by solvent extraction, obtaining good extraction yields (>91%) and satisfactory precision values (RSD<4.8%). The method was successfully applied to DBS samples collected from some cocaine users, both with and without concomitant ethanol intake. The results were in good agreement with those obtained from plasma samples subjected to an original solid-phase extraction procedure on C8 cartridges. The method has demonstrated to be suitable for the monitoring of cocaine/ethanol use by means of DBS or plasma testing. Assays are in progress to apply this method on the street, for the control of subjects suspected of driving under the influence of psychotropic substances.     

十二烷基苯磺酸钠的超声降解研究

采用频率为１．８ＭＨｚ,声强近似为５Ｗ·ｃｍ~－２的超声波,在固定式声化学的应器内研究了初始浓度为２００ｍｇ／Ｌ－４００ｍｇ／Ｌ的十二烷基苯磺酸钠（ＤＢＳ）溶液的声化学降解情况．实验表明,浓度的改变对ＴＯＣ的削减率无明显的影响,溶液的ＰＨ值对降解率则有显著影响,碱性条件下（ＰＨ＝１３）,ＤＢＳ几乎无降解,酸性条件下（ＰＨ＝３）ＴＯＣ削减率≤１０％．通过分析降解过程中溶液的紫外光谱（１９０－３４０ｎｍ）,发现降解过程中有复杂的中间产物生成,包括小分子烃类碎片及硝基化合物。我们认为,能使溶液表面张力。降低的表面活性剂,其声化学降解率低的原因在于,溶液表面张力下降后影响了溶液中空化效应的产生,从而降低了溶液中声化学反应的强度,致使ＴＯＣ削减率不高。     

Quantitative analysis of clofazimine (Lamprene®), an antileprosy agent,in human dried blood spots using liquid chromatography–tandem mass spectrometry

An LC–MS/MS method was developed and validated for bioanalysis of clofazimine in human dried blood spot (DBS) samples in support of a clinical study on multidrug‐resistant tuberculosis in developing countries. The validated assay dynamic range was from 10.0 to 2000 ng/mL using a 1/8 inch DBS punch. The accuracy and precision of the assay were ±11.0% (bias) and ≤13.5% (CV) for the LLOQs (10.0 ng/mL) and ±15% (bias) and ≤15% (CV) for all other QC levels. The assay was proved to be free from the possible impact owing to spot size and storage temperature (e.g. at 60°C, ≤ − 60°C). The validated assay is well suited for the intended clinical study where conventional pharmacokinetic sample collection is not feasible.     

Volumetric Absorptive Microsampling of Blood for Untargeted Lipidomics

In the present, proof-of-concept paper, we explore the potential of one common solid support for blood microsampling (dried blood spot, DBS) and a device (volumetric absorptive microsampling, VAMS) developed for the untargeted lipidomic profiling of human whole blood, performed by high-resolution LC-MS/MS. Dried blood microsamples obtained by means of DBS and VAMS were extracted with different solvent compositions and compared with fluid blood to evaluate their efficiency in profiling the lipid chemical space in the most broad way. Although more effort is needed to better characterize this approach, our results indicate that VAMS is a viable option for untargeted studies and its use will bring all the corresponding known advantages in the field of lipidomics, such as haematocrit independence.