Latest ArticlesVancomycin has been widely prescribed as the first-line antibiotic in the treatment of methicillin-resistant Staphylococcus aureus and other serious Gram-positive infections. Due to its large pharmacokinetic (PK) variability and narrow therapeutic range, it requires optimization of dosage to achieve target exposure. In this study, SmartDose, a decision support system for individualization of vancomycin dosage is developed using the maximum a posterior Bayesian estimation (MAPB) by the open-source language R combined with the population PK characteristics of vancomycin in Chinese patients. It provides initial design and adjustment of dose regimens based on the therapeutic drug monitoring (TDM) results, as well as a user-defined module to facilitate optimal vancomycin therapy. SmartDose has a high computational reliability, which is validated by NONMEM, the golden standard PK software. Meanwhile, SmartDose is established as a web-based application and its operational flexibility makes it an efficient tool for vancomycin dose optimization in routine clinical settings.
The Chinese herbal Sophora alopecuroides is widely used to clean intestine and eliminate dampness, and it has good therapeutic effects on treating bacillary dysentery and inflammatory bowel disease, etc. in clinics. However, the mechanism of treatment is not yet well understood. The present study was aimed to explore the mechanism of Sophora alopecuroides treatment of large intestine dampness-heat syndrome (LIDHS). The LIDHS model was performed by the comprehensive factors, including high temperature and humidity environment, high-sugar and high-fat diet, and intraperitoneal injection of Escherichia coli. The blood routine, serum proinflammatory cytokine levels and histopathological changes of intestine were detected and observed. Meanwhile, the serum metabolomic approach was conducted using the method of ultra performance liquid chromatography coupled to quadrupole time-of-flight mass/mass spectrometry (UHPLC-Q/TOF-MS/MS). The results showed that Sophora alopecuroides has good therapeutic effects on the LIDHS rat models. After treatment with Sophora alopecuroides, the abnormality of blood routine indexes as well as proinflammatory cytokines, including IL-1β, IL-2, IL-6 and TNF-α in vivo, tended to be normal, and the histopathological changes of intestine were improved. Through metabolic profiling and protocol analysis, 9 potential metabolic markers may be closely related with the treatment mechanism of Sophora alopecuroides on this disease, including taurine, L-tryptophan, LysoPE, LysoPC, LPA, DG, chenodeoxycholic acid disulfate, traumatic acid and 7-ketodeoxycholic acid, which were involved in taurine and hypotaurine metabolism, glycerophospholipid metabolism, glycerolipid metabolism, tryptophan metabolism and primary bile acid biosynthesis etc. The serum metabolomic approach can be applied to clarify the therapeutic mechanism of Sophora alopecuroides on LIDHS, and provide the theoretical basis for Sophora alopecuroides in clinical practice.
An LC-MS/MS method was developed for the simultaneous determination of fosaprepitant and aprepitant in human plasma, and applied to a pharmacokinetic study of 150 mg fosaprepitant dimeglumine injection to 12 Chinese healthy volunteers. The analytes and internal standards were extracted from plasma by protein precipitation with acetonitrile and separated on a Cortex C18+ (50 mm×2.1 mm, 2.7 μm) column using a gradient elution procedure. Mass spectrometry was performed in negative MRM mode, and parent-to-produce transitions were as follows:m/z 613.1→78.9 for fosaprepitant, m/z 617.0→78.9 for d4-fosaprepitant, m/z 533.2→275.1 for aprepitant and m/z 537.2→279.1 for d4-aprepitant. Plasma sample was basified to stabilize fosaprepitant. The standard curves were demonstrated to be liner in the range of 15.0 to 6 000 ng·mL-1 for fosaprepitant and 10.0 to 4 000 ng·mL-1 for aprepitant. The intra-day precisions and inter-day precisions and accuracy were within the acceptable limits for all concentrations.
Severe acute pancreatitis (SAP) is characterized by both local and systemic inflammatory responses. This study was designed to develop a site-specific delivery strategy for SAP therapy using celastrol (CLT). First, murine RAW264.7 cells were used as a model of macrophage cell line, cell membranes were obtained by emptying intracellular contents via hypotonic lysing, mechanical membrane disruption, and differential centrifugation. Poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NPs) were then prepared by sonication. With the collected membrane materials, macrophage membrane coated PEG-PLGA NPs (RNPs) were then prepared by extrusion through a 400 nm polycarbonate membrane. Biodistribution study in rats with SAP showed RNPs selectively accumulated in the inflamed pancreatic tissues. Compared with CLT loaded NPs, CLT loaded RNPs were proven to effectively attenuate local pancreatic inflammation and systemic inflammation in rats with SAP.
Honokiol (HK) have extensive pharmacological activities, but its poor solubility and instability restricted its clinical application and efficacy exertion. HK nanosuspensions (HK-NSps) were designed in this study in order to solve the problems. HK-NSps were prepared by antisolvent precipitation method, using poly-vinylpyrrolidone (PVP) and bovine serum albumin (BSA) as a combined stabilizer. The particle size was measured using dynamic light scattering method, the morphology was observed by transmission electron microscopy. The size change and drug content of HK-NSps in various physiological media during the storage at ambient temperature was examined to evaluate their storage stability. Dialysis method was used to study their drug release in vitro. MTT assay was used to assess their in vitro cytotoxicity against 4T1 breast cancer cell line. Anti-tumor effect in vivo was also investigated in 4T1 tumor-bearing mice. HK-NSps were prepared with high drug loading content of 48.62%, nearly spherical shape and good storage stability. The average particle size was (83.40 ±1.042) nm, the polydispersity index (PDI) value was 0.223 ±0.011, the zeta potential was (-42.2 ±1.2) mV. HK-NSps showed sustained in vitro drug release and enhanced cytotoxicity in contrast to free HK against 4T1 cells (IC50, 8.36 μg·mL-1 vs 37.58 μg·mL-1, P < 0.05). The in vivo study on 4T1 tumor-bearing mice demonstrated that HK-NSps showed good dose-dependent tumor inhibition rate (TIR). In contrast to 4 mg·kg-1 of PTX injection (TIR, 47.9%), medium and high dose of HK-NSps displayed improved therapeutic efficacy (TIR, 55.67% for 40 mg·kg-1, 67.28% for 60 mg·kg-1, P < 0.05). In contrast, the high dose of HK crude drug (60 mg·kg-1) had TIR of only 54.13% even administrated every day. In conclusion, HK-NSps were prepared with small size, high drug-loading capacity, and good stability. The improved in vitro and in vivo antitumor efficacy demonstrated that HK can be a promising antitumor drug in combination with nanosuspensions technology.
Safflower is a dried flower of the annual herbaceous plant safflower (Carthamus tinctorius L.). As a traditional Chinese medicine, it was widely used in the regulation of blood circulation. Flavonoids are the main active ingredients in safflower. MYB transcription factors are involved in the regulation of flavonoids. The cloning and expression analysis of MYB transcription factor genes in safflower is of great significance, not only for clarifying the regulation mechanism of flavonoids biosynthesis in safflower, but also for the artificial regulation of flavonoid biosynthesis in safflower. Based on the transcriptome data, we used iTAK to annotate the MYB transcription factors in safflower. The MYB transcription factors were cloned and their sequences were analyzed. Besides, their expressions were analyzed by a Real-time PCR. In the experiment, eight long fragment MYB transcription factors were screened and six MYB transcription factors was successfully cloned, named CtMYB-TF1, CtMYB-TF2, CtMYB-TF4, CtMYB-TF5, CtMYB-TF6 and CtMYB-TF7, respectively. The six MYB transcription factors had the core domain of MYB transcription factor family, and evolutionary analysis showed that the CtMYB-TF7 transcription factor was closely related to the factors AtMYBL2 and AtMYB12. Expression analysis showed that the expression of CtMYB-TF5, CtMYB-TF6 and CtMYB-TF7 was low in roots, stems and leaves, and was high in the flower. The results provide a foundation for study of mechanism of molecular regulation of safflower flavonoids.
Currently, the specification grading standard for Astragali Radix can not accurately reflect growth years. The aim of this study is to identify the growth ring number of different parts of 1 to 6 year Hengshan imitative wild culture Astragali Radix, in order to get a different absolute growth years, to classify the accumulation rules of the content of flavonoids and saponins, and to lay the foundation for evaluating quality of Astragali Radix. Observing growth ring numbers of 1-6 years Astragali Radix by means of hand sections and paraffin sections in the study, and analyzing the number of different growth years and different diameter. At the same time, HPLC-UV-ELSD was used to analyze the 12 index components of the samples with absolute growth years of 2 to 6 years. The results indicated that the growth ring number excepting hollow part is consistent with the actual growth period of Astragali Radix and the number of growth rings gradually decreased from the upper to lower. The results of HPLC-UV-ELSD determination showed that the saponins content of 3-year-old Astragali Radix was the highest while the flavonoids content of the 4-year-old reached the maximum. The study provided the basis for foundation of the specification grading standard for Astragali Radix and clinical rational use drug.
The success rate of mechanism-based drug discovery depends on the drug targets. With the rapid development of genomics and proteomics, a lot of nonenzymic proteins have been identified as potential drug targets. However, these nonenzymic proteins cannot be regulated by occupying the active site, which were recognized as undruggable targets. Direct regulation of the concentration of these proteins in cells by the innate ubiquitin-proteasome is a potential approach to target these proteins. The ubiquitination of target protein by E3 ligase is the key step for ubiquitin-proteasome mediated protein degradation. Proteolysis targeting chimeras (PROTACs) can facilitate the assembly of complex that consists of the target protein and E3 ligase. The target protein will be ubiquitinated, leading to the degradation by proteasome. This type of regulation mechanism can expand the scope of potential drug targets, and the development of PROTACs may be an innovative strategy in drug discovery.
Ferroptosis is a novel type of cell death which induced by iron-dependent lipid peroxidation accumulation. This type of cell death is significantly different from other cell death in terms of morphology, genetics and biochemistry. It has been reported that ferroptosis is involved in a variety of human diseases, particularly in liver diseases. Therefore, screening and studying of inhibitors or activators of ferroptosis may provide novel strategies for prevention and treatment of liver diseases. This review provides the biological characteristics and regulatory signaling pathways of ferroptosis, as well as the relationship between ferroptosis and liver diseases, which will contribute to new insight into the pathogenesis of liver diseases.
Depression is a complex heterogeneous psychiatric disorder with a potential to cause patient disability worldwide. In the past decades, a number of the first-line drugs (tricyclics, monoamine oxidase inhibitors, serotonin selective reuptake inhibitors, noradrenaline reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, etc.) had been discovered for the treatment of depression. CYP450 superfamily is involved in the biotransformation of antidepressants mainly through the CYP2D6, CYP2C19, CYP3A4 isoenzymes. Their genetic polymorphisms are closely related to clinical use and the interactions have been already identified between enzymes and antidepressants. This review focuses on drug metabolism and the interaction for CYP450 enzymes. The content may contribute to the development of antidepressant, improvement of the safety of antidepressants and the efficacy of treatment.
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