Method for determination of elemental impurities in metronidazole benzoate using inductively coupled plasma mass spectrometry.

The elemental impurities in pharmaceutical products have aroused widespread concern among respective supervising authorities and official pharmacopoeias since they are harmful and have no therapeutic effects. Metronidazole benzoate is used extensively to treat a variety of infections. However, impurities will inevitably be introduced in the manufacturing process of metronidazole benzoate. Hence, in this study, a sensitive method was developed for trace determination of elemental impurities in metronidazole benzoate active pharmaceutical ingredients by using inductively coupled plasma mass spectrometry in kinetic energy discrimination mode. The method was validated for system suitability, specificity, linearity, sensitivity, accuracy, and precision according to USP chapter <233> Elemental Impurities-Procedure. The method had good linearity with correlation coefficients > 0.99. The limits of detection were in the range of 0.0003-0.1411 µg/g, which was lower than the acceptable limit and indicated the high sensitivity of the method. The method was accurate with the recoveries in the range of 92%-107%. Moreover, the content of seven elemental impurities in the three batches of metronidazole benzoate active pharmaceutical ingredients by this method was originally below their limits and less than 30% of permitted daily exposure, meeting the requirement of International Council for Harmonization Q3D guidelines. Thus, this newly developed and validated method for estimating elemental impurities in metronidazole benzoate active pharmaceutical ingredients was within the permitted limit and suitable for routine use.

Preparation and Product Characterization of Microwaveable Food Using Lentinus edodes Protein through 3D Printing.

The Lentinus edodes protein (LP) is a high-quality protein known for its well-balanced amino acid composition. In this study, we developed three-dimensional (3D)-printed microwaveable food using a combination of LP and potato flour, and optimized the formulation to achieve a ratio of LP: potato flour: xanthan gum: water = 2:8:1:23. The 3D-printed samples exhibited better shape, weight, and size compared to the molded samples after microwave treatment, with the most favorable microwave effect observed at a 90% filling ratio. The LP content affected the viscosity and retrogradation value of the LP-potato starch mixture. Microwave duration affected the surface hardness, interior softness, and moisture content of the product. The highest overall score of 8.295 points was obtained with a microwave processing duration of 2 min. This study lays a foundation for the development of LP-based 3D-printed food.

Unveiling the Therapeutic Potentials of Mushroom Bioactive Compounds in Alzheimer's Disease.

Alzheimer's disease (AD) stands as a prevailing neurodegenerative condition (NDs), leading to the gradual deterioration of brain cells and subsequent declines in memory, thinking, behavior, and emotion. Despite the intensive research efforts and advances, an effective curative treatment for the disease has not yet been found. Mushrooms, esteemed globally for their exquisite flavors and abundant nutritional benefits, also hold a wealth of health-promoting compounds that contribute to improving AD health. These compounds encompass polysaccharides, proteins, lipids, terpenoids, phenols, and various other bioactive substances. Particularly noteworthy are the potent neuroprotective small molecules found in mushrooms, such as ergothioneine, erinacine, flavonoids, alkaloids, ergosterol, and melanin, which warrant dedicated scrutiny for their therapeutic potential in combating AD. This review summarizes such positive effects of mushroom bioactive compounds on AD, with a hope to contribute to the development of functional foods as an early dietary intervention for this neurodegenerative disease.

Preparation and characterization of 3D-printed antibacterial hydrogel with benzyl isothiocyanate.

Benzyl isothiocyanate (BITC) is an isothiocyanate of plant origin, especially the mustard family, which has good antibacterial properties. However, its applications are challenging due to its poor water solubility and chemical instability. We used food hydrocolloids, including xanthan gum, locust bean gum, konjac glucomannan, and carrageenan as three-dimensional (3D)-printing food ink base and successfully prepared 3D-printed BITC antibacterial hydrogel (BITC-XLKC-Gel). The characterization and fabrication procedure of BITC-XLKC-Gel was studied. The results show that BITC-XLKC-Gel hydrogel has better mechanical properties by low-field nuclear magnetic resonance (LF-NMR), mechanical properties, and rheometer analysis. The strain rate of BITC-XLKC-Gel hydrogel is 76.5%, which is better than that of human skin. Scanning electron microscope (SEM) analysis showed that BITC-XLKC-Gel has uniform pore size and provides a good carrier environment for BITC carriers. In addition, BITC-XLKC-Gel has good 3D-printing performance, and 3D printing can be used for customizing patterns. Finally, inhibition zone analysis showed that the BITC-XLKC-Gel added with 0.6% BITC had strong antibacterial activity against Staphylococcus aureus and the BITC-XLKC-Gel added with 0.4% BITC had strong antibacterial activity against Escherichia coli. Antibacterial wound dressing has always been considered essential in burn wound healing. In experiments that simulated burn infection, BITC-XLKC-Gel showed good antimicrobial activity against methicillin-resistant S. aureus. BITC-XLKC-Gel is a good 3D-printing food ink attributed to strong plasticity, high safety profile, and good antibacterial performance and has great application prospects.

Method for trace determination of N-nitrosamines impurities in metronidazole benzoate using high-performance liquid chromatography coupled with atmospheric-pressure chemical ionization tandem mass spectrometry.

Genotoxic impurity control has been a great concern in the pharmaceutical industry since the recall of the large round of sartans worldwide in 2018. In these sartans, N-nitrosamines were the main contaminants in active pharmaceutical ingredients and formulations. Numerous analytical methods have been developed to detect N-nitrosamines in food, drugs, and environmental samples. In this study, a sensitive method is developed for the trace determination of N-nitrosamine impurities in metronidazole benzoate pharmaceuticals using high-performance liquid chromatography/atmospheric-pressure chemical ionization tandem mass spectrometry in the multiple reaction monitoring mode. The method was validated regarding system suitability, selectivity, linearity, accuracy, precision, sensitivity, solution stability, and robustness. The method showed good linearity with R2 ≥ 0.999 and FMandel  < Ftab(95%) ranging from 0.33 to 8.00 ng/ml. The low limits of detection of N-nitrosamines were in the range of 0.22-0.80 ng/ml (0.0014-0.0050 ppm). The low limits of quantification were in the range of 0.33-1.20 ng/ml (0.0021-0.0075 ppm), which were lower than the acceptable limits in metronidazole benzoate pharmaceuticals and indicated the high sensitivity of the method. The recoveries of N-nitrosamines ranged from 84% to 97%. Thus, this method exhibits good selectivity, sensitivity, and accuracy. Moreover, it is a simple, convenient, and scientific strategy for detecting N-nitrosamine impurities in pharmaceuticals to support the development of the pharmaceutical industry.

Verbascoside: An Efficient and Safe Natural Antibacterial Adjuvant for Preventing Bacterial Contamination of Fresh Meat.

Inappropriate and disproportionate antibiotic use contributes immensely to the development of antibiotic resistance in bacterial species associated with food contamination. Therefore, alternative strategies to treat multidrug-resistant (MDR) bacterial infections are urgently needed. In this study, verbascoside was shown to exhibit excellent antibacterial activity and synergistic effects in combination with cell wall synthesis-inhibiting antibiotics, indicating that it can be used as an adjuvant to restore or increase the activity of antibiotics against resistant pathogens. In a mechanistic study, higher concentrations of verbascoside resulted in a longer lag phase and a lower specific exponential-phase growth rate of bacteria. Furthermore, verbascoside exerted its antimicrobial activity through multiple mechanisms, including cell membrane dysfunction, biofilm eradication and changes in cell morphology. The promising antibacterial activity and in vitro safety assessment results suggested that verbascoside can be used as a food additive for fresh meat preservation. Treatment with medium and high doses of verbascoside caused significant bacterial death in meat samples, slowed the spoilage rate, and extended the shelf life. Collectively, verbascoside is expected to be useful as an antibiotic adjuvant to prevent or treat resistant bacteria-related infections and an alternative novel antimicrobial additive in the food industry.

Syringa microphylla Diels: A comprehensive review of its phytochemical, pharmacological, pharmacokinetic, and toxicological characteristics and an investigation into its potential health benefits.

BACKGROUND: Syringa microphylla Diels is a plant in the family Syringa Linn. For hundreds of years, its flowers and leaves have been used as a folk medicine for the treatment of cough, inflammation, colds, sore throat, acute hepatitis, chronic hepatitis, early liver cirrhosis, fatty liver, and oesophageal cancer. PURPOSE: For the first time, we have comprehensively reviewed information on Syringa microphylla Diels that is not included in the Pharmacopoeia, clarified the pharmacological mechanisms of Syringa microphylla Diels and its active ingredients from a molecular biology perspective, compiled in vivo and in vitro animal experimental data and clinical data, and summarized the toxicology and pharmacokinetics of Syringa microphylla Diels. The progress in toxicology research is expected to provide a theoretical basis for the development of new drugs from Syringa microphylla Diels, a natural source of compounds that are potentially beneficial to human health. METHODS: The PubMed, Google Scholar, China National Knowledge Infrastructure, Web of Science, SciFinder Scholar and Thomson Reuters databases were utilized to conduct a comprehensive search of published literature as of July 2021 to find original literature related to Syringa microphylla Diels and its active ingredients. RESULTS: To date, 72 compounds have been isolated and identified from Syringa microphylla Diels, and oleuropein, verbascoside, isoacteoside, echinacoside, forsythoside B, and eleutheroside B are the main active components. These compounds have antioxidant, antibacterial, anti-inflammatory, and neuroprotective effects, and their safety and effectiveness have been demonstrated in long-term traditional applications. Molecular pharmacology experiments have indicated that the active ingredients of Syringa microphylla Diels exert their pharmacological effects in various ways, primarily by reducing oxidative stress damage via Nrf2/ARE pathway regulation, regulating inflammatory factors and inducing apoptosis through the MAPK and NF-κB pathways. CONCLUSION: This comprehensive review of Syringa microphylla Diels provides new insights into the correlations among molecular mechanisms, the importance of toxicology and pharmacokinetics, and potential ways to address the limitations of current research. As Syringa microphylla Diels is a natural low-toxicity botanical medicine, it is worthy of development and utilization and is an excellent choice for treating various diseases.

Introducing High Density of Very Active Sites and Stepwise Postmodification for Tailoring the Porosity of Highly Demanding Cr3+-Based Metal-Organic Frameworks.

Chromium(III)-based metal-organic frameworks (Cr-MOFs) are highly robust and porous and have been very attractive in a wide range of investigations. However, the harsh direct synthetic conditions not only impede the synthesis of new Cr-MOFs but also restrict the introduction of functional groups into them. Postsynthetic modification has somewhat alleviated such difficulties; nevertheless, it still suffered from procedures that are tedious and conditions that are not mild, which often result in low concentration of the functional groups introduced. To overcome these shortcomings, here, in this paper, we supplied a new route and prepared a benzyl alcohol functionalized Cr-SXU-2 from the judiciously designed benzyl alcohol functionalized Fe-SXU-2 through solvent-assisted metal metathesis strategy. The functionalized Cr-SXU-2 shows well-preserved crystallinity, porosity, and high chemical stability. The benzyl alcohol group can be converted into a very active benzyl bromide group in an almost quantitative yield and thus for the first time produce the benzyl bromide functionalized MOF, Cr-SXU-2-Br, in which the -Br group can be exchanged by a nucleophilic group. As a proof of concept, -N3 was introduced and transformed into other active sites via "click reaction" to further tailor the interior of Cr-SXU-2. All these functionalized Cr-MOFs showed improved adsorption performance in contrast to the nonfunctionalized one. This step-by-step postmodification process not only diversifies the functionalization of robust MOFs but also opens a new route to employ many different functional groups in the demanding highly stable Cr-MOF platforms.

Anti-HSV-1 effect of dihydromyricetin from Ampelopsis grossedentata via the TLR9-dependent anti-inflammatory pathway.

OBJECTIVES: Herpes simplex virus 1 (HSV-1) is one of the most prevalent viruses in humans worldwide. Owing to limited therapeutic options mainly with acyclovir (ACV) and analogues and the emergence of ACV-resistant strains, new drugs with different modes of action and low toxicity are required. The aim of this study was to determine the anti-HSV-1 effect and mechanism of action of the flavonoid compound dihydromyricetin (DHM) from Ampelopsis grossedentata. METHODS: The HSV-1 inhibitory effect of DHM was evaluated by measuring plaque formation and generation of progeny virus as well as expression of HSV-1-related genes in Vero cells. The molecular mechanism of the antiviral activity of DHM against HSV-1 was explored by real-time quantitative PCR and ELISA. RESULTS: DHM presented a significant inhibitory effect on HSV-1 plaque formation and generation of progeny virus, with an EC50 (50% effective concentration) of 12.56 µM in Vero cells. Furthermore, expression of HSV-1 immediate-early genes (ICP4 and ICP22), early genes (ICP8 and UL42) and late genes (gB, VP1/2) was decreased by DHM at concentrations of 16 µM and 32 µM. DHM specifically suppressed mRNA levels of Toll-like receptor 9 (TLR9), leading to inhibition of the inflammatory transcriptional factor NFκB and a decrease in TNFα. CONCLUSION: These findings indicate that the effective inhibitory activity of DHM was achieved by suppressing TNFα production in a TLR9-dependent manner. Although further studies are needed to better characterise the activity of DHM in vivo, the results suggest this extract as a promising new anti-HSV-1 agent.

Preparation of a nanoscale dihydromyricetin-phospholipid complex to improve the bioavailability: in vitro and in vivo evaluations.

Dihydromyricetin (DMY), a flavanonol compound found as the most abundant and bioactive constituent in Ampelopsis grossedentata (Hand-Mazz) W.T. Wang, possesses numerous pharmacological activities, such as antioxidant, anti-inflammation, anticancer, anti-microbial, hypoglycemic and hypolipidemic effects, and so on. Recently, DMY shows a promising potential to develop as an agent for the prevention and treatment of Type 2 diabetes mellitus (T2DM). However, the low oral bioavailability of DMY was one of the special concerns to be resolved for its clinical applications. In this study, DMY phospholipid complex (DMY-HSPC COM) was prepared by the solvent evaporation technique and optimized with DMY combination ratio. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrophotometry (FT-IR) were carried to characterize the formation of DMY-HSPC COM. The particle size, zeta potential, drug loading and solubility of DMY-HSPC COM were further investigated. The phospholipid complex technology could significantly improve the solubility of DMY. Pharmacokinetic study results of DMY-HSPC COM in healthy SD rats and T2DM rats demonstrated that the oral bioavailability was significantly increased when compared with pure DMY as well, which could be attributed to the improvement of the aqueous solubility of the complex, absorption promotion and a probable decrease in intestinal and hepatic metabolism. In addition, when compared with healthy SD rats, pharmacokinetic parameters of pure DMY and DMY-HSPC COM showed significant difference in T2DM rats. Thus, phospholipid complex technology holds a promising potential for increasing the oral bioavailability of DMY.

Uptake and Transport Mechanism of Dihydromyricetin Across Human Intestinal Caco-2 Cells.

A variety of beneficial pharmacological activities have been reported for dihydromyricetin (DMY), however, its oral bioavailability is poor and the intestinal absorption profiles of DMY remains unknown. The aim of this study was to investigate the uptake and transport mechanism of DMY in human intestinal Caco-2 cells. DMY was detected using a liquid chromatography-tandem mass spectrometry method. Several factors including time, concentration, pH, temperature and efflux transporters were systematically evaluated. DMY was poorly absorbed by a passive diffusion mechanism. The uptake and transport of DMY were time and concentration dependent. Interestingly, decreasing the pH from 8.0 to 6.0 markedly enhanced the DMY uptake, but didn't significantly affect its bidirectional transport. Efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein also influenced the DMY uptake and transport processes. This work details the uptake and transport characteristics of DMY and provides basis for future study. PRACTICAL APPLICATION: This study elucidated the uptake and transport characteristics of dihydromyricetin (DMY). DMY was poorly absorbed by a passive diffusion mechanism. The uptake and transport of DMY were time and concentration dependent. Interestingly, pH affected DMY uptake but not its bidirectional transport. MRP2 and BCRP were involved in the uptake and transport of DMY, which hindered the absorption of DMY in the intestinal. Thus, the present study may provide useful information for designing DMY delivery systems and avoiding DMY-drug interactions.

Berbamine suppresses cell proliferation and promotes apoptosis in ovarian cancer partially via the inhibition of Wnt/ß-catenin signaling.

Ovarian cancer is a common and lethal cancer affecting women globally. Berbamine is a natural compound from the plant Berberis amurensis, which is used in Chinese traditional medicine. Recent studies have shown the anti-tumor effects of berbamine in several types of cancers but not in ovarian cancer. In the present study, we investigated the potential anti-tumor effects of berbamine in ovarian cancer and explored the underlying molecular mechanisms. Berbamine suppressed the cell viability of ovarian cancer cells in a concentration-dependent manner as revealed by methyl thiazolyl tetrazolium assay. Berbamine also suppressed the cell growth and invasion of ovarian cancer cells as measured by colony formation and cell invasion assays, respectively. Flow cytometry experiments showed that berbamine increased cell apoptotic rate and induced cell cycle arrest at G0/G1 phase in ovarian cancer cells. Western blot analysis showed that berbamine increased the protein levels of cleaved caspase-3, cleaved caspase-9, Bax, and decreased the protein level of Bcl-2 in ovarian cancer cells. Quantitative real-time PCR and western blot analysis demonstrated that berbamine treatment inhibited the Wnt/ß-catenin signaling in ovarian cancer cells. The inhibitory effects of berbamine on cell viability and invasion of ovarian cancer cells can be partially reversed by lithium chloride (LiCl) treatment. Growth of tumors developed from SKOV3 cells was significantly suppressed in berbamine-treated group, and berbamine treatment enhanced caspase-3 and -9 cleavage and reduced ß-catenin protein level in tumor tissues. In summary, berbamine exerts its anti-cancer effects in vitro and in vivo via induction of apoptosis, partially associated with the inhibition of Wnt/ß-catenin signaling.

Interactions of Dihydromyricetin, a Flavonoid from Vine Tea (Ampelopsis grossedentata) with Gut Microbiota.

Dihydromyricetin (DMY) is the main bioactive constituent in vine tea (Ampelopsis grossedentata), which was predominantly distributed in the gastrointestinal tract and showed poor oral bioavailability. Our aim was to systematically investigate the interactions of DMY with gut microbiota. Through the metabolism study of DMY by fecal microflora in vitro, it was found that DMY could be metabolized into three metabolites by fecal microflora via reduction and dehydroxylation pathways, and the dehydroxylation metabolite was the dominant one. Meanwhile, in order to consider the influence of gut microbiota metabolism on the pharmacokinetics of DMY, the pharmacokinetics of DMY in control and pseudo-germ-free rats were compared. It was shown that area under the curve (AUC) could only slightly increase, however, peak concentration (Cmax ) could significantly increase in the pseudo-germ-free rats compared with the control rats, which indicated the gut microbiota metabolism played an important role in the pharmacokinetics of DMY. In addition, the long-term influence of DMY on gut microbiota composition by using 16S rRNA pyrosequencing was further investigated. And it was found that DMY could markedly alter the richness and diversity of the gut microbiota and modulate the gut microbiota composition. The present findings will be helpful for the future development and clinical application of DMY. PRACTICAL APPLICATION: The gut microbiota plays an important role in the pharmacokinetics of flavonoids. As well, the long-term supplements of flavonoids could alter the gut microbiota composition in turn. The study aims to clarify the mutual interaction of DMY with gut microbiota, which may lead to new information with respect to the mechanism study and clinical application of DMY.

Approaches to developing fast release pellets via wet extrusion-spheronization.

Microcrystalline cellulose (MCC) is widely regarded as the excellent choice to manufacture pellets via wet extrusion-spheronisation (ES) process due to its excellent water uptake capability, water holding capacity, desirable rheological properties, cohesiveness and plasticity etc. Nevertheless, in spite of all these advantages, limitations associated with the application of MCC also have been reported. The most prevailing limitation is prolonged or incomplete drug release profile due to the lack of disintegration as pellet contracts significantly during the drying process, especially when in combination with poorly soluble drug at a high level. This characteristic limits the application of MCC in immediate release formulations. Over the years, many approaches have been tried to overcome this disadvantage, such as modifying MCC, incorporation of superdisintegrant, increasing the porosity of pellet, partial or complete substitution for MCC, enhancing the solubility of poorly soluble drug (e.g. solid dispersion, self-emulsifying drug-delivery system), etc. In this review, we will provide an updated and integrated discussion of current approaches to prepare fast release pellets via wet ES.

Berbamine suppresses cell viability and induces apoptosis in colorectal cancer via activating p53-dependent apoptotic signaling pathway.

Berbamine has been shown to exhibit anti-cancer activities in various types of cancers. The effects of berbamine on colorectal colon cancer (CRC) have not been examined, and the present study aimed to investigate the anti-cancer effects of berbamine in CRC and explore its underlying molecular mechanisms. The effect of berbamine on the CRC cells was determined by MTT assay. Flow cytometry was performed to examine the effect of berbamine on cell apoptosis and cell cycle as well as mitochondrial membrane potential in CRC cell lines. The specific apoptosis-related factors were evaluated by western blot assay. In vivo anti-cancer effect of berbamine was assessed in SW480 xenografts. Berbamine suppressed the cell viability of CRC cells in concentration-dependent and time-dependent manners. Flow cytometry experiments showed that berbamine increased cell apoptotic rate and induced cell cycle arrest at G0/G1 phase. Berbamine treatment also decreased the mitochondrial membrane potential in CRC cells. Western blot assay showed that berbamine increased the protein levels of p53, caspase-3, caspase-9, Bax and poly ADP ribose polymerase, and decreased the protein levels of Bcl-2 in CRC cells. Berbamine failed to increase the cell apoptotic rate in p53 mutant CRC cell lines. Tumor growth by grafted SW480 cells were significantly suppressed in berbamine group. Expression of p53, caspase-3 and -9 in tumor tissues was significantly up-regulated by berbamine. Berbamine exerts anti-cancer effects in vitro and in vivo via induction of apoptosis, partially associated with the activation of p53-dependent apoptosis signaling pathway.

Tissue Distribution, Excretion, and Metabolic Profile of Dihydromyricetin, a Flavonoid from Vine Tea (Ampelopsis grossedentata) after Oral Administration in Rats.

Dihydromyricetin (DMY), a flavanonol compound found as the most abundant and bioactive constituent in vine tea (Ampelopsis grossedentata), possesses numerous biological activities. In the present study, an HPLC-MS/MS method for the determination of DMY in tissues, urine, and feces was developed and applied to the tissue distribution and excretion study after oral administration in rats, and the metabolic profile of DMY was further investigated using UPLC-QTOF-MS. The results indicated that DMY could be distributed rapidly in various tissues and highly in the gastrointestinal tract. The elimination of DMY occurred rapidly as well, and most unconverted forms were excreted in feces. A total of eight metabolites were identified in urine and feces, while metabolites were barely found in plasma. The predicted metabolic pathways including reduction, dehydroxylation, methylation, glucuronidation, and sulfation were proposed. The present findings may provide the theoretical basis for evaluating the biological activities of DMY and will be helpful for its future development and application.

Gastrointestinal stability of dihydromyricetin, myricetin, and myricitrin: an in vitro investigation.

The gastrointestinal (GI) stability of three flavonoids, dihydromyricetin (DMY), myricetin (MYR), and myricitrin (MYT), was examined in simulated physiological fluids. Several factors that may influence the degradation rate of theses flavonoids were evaluated, including pH and the presence of pepsin and pancreatin enzymes. We found that GI stability followed the order of MYT > DMY > MYR. These flavonoids were stable in simulated gastric fluids and buffer solutions (pH 1.2), but encountered a pseudo-first-order kinetic degradation in simulated intestinal fluids and buffer solutions (pH 6.8). We conclude that it is the pH, rather than the presence of pepsin or pancreatin, which most strongly influences the stability of these three flavonoids. Further study of the stability of the compounds using a pH range (1.0-8.0) indicated potential instability in the duodenum, small intestine, and colon. Therefore, we conclude that the low bioavailability of these flavonoids may be due to their poor stability in the GI tract.

Shear Stress-sensitive Carriers for Localized Drug Delivery.

Stenosis of the critical blood vessels, which occurs in a variety of cardiovascular and cerebrovascular diseases, is one of leading causes of death in the world. Vascular stenosis will significantly alter the hemodynamic features in the vessel. Hemodynamic shear stress, one of the most important physical parameters of blood flow, will be dramatically elevated at the stenotic site. When platelets flow through the constricted site, they will sense these abnormally high shear stresses, and then respond by activating, sticking to the vascular wall, and aggregating at these sites. The shear-dependent platelet activation inspired a novel targeting platform-shear stress activated drug targeting delivery. The shear-activated drug delivery systems preferentially release their content under elevated shear stress, providing a novel approach to cure various diseases, in particular, cardiovascular diseases. In this review, we, on one hand, introduced the features of hemodynamic shear stress under both physiological and pathological conditions. On the other hand, we summarized the carriers displaying sensitivity to shear stress, such as liposomes, aggregations, gels, emulsions, in addition to the factors affecting the mechanical properties of them. Lastly, the clinical applications and prospects of this novel drug targeting strategy were discussed. It is hoped that, with a better understanding of shear stress-sensitive carriers and their targeted principle, a novel targeted drug delivery strategy will be one day applied in the clinics of the future.

[Analysis and exploration on adverse reactions of four kinds of andrographolide injections].

Concerned literature on four kinds of andrographolide injections in recent 15 years were searched in CNKI, Wanfang and VIP databases. The adverse drug reaction(ADR) cases of Chuanhuning, Yanhuning, Xiyanping and Lianbizhi injections were classified and analyzed statistically, including a total of 194 articles and 3 479 cases. The ADR clinical characteristics and occurrence regularity of these four andrographolide injections were analyzed and compared from the gender, age, primary disease, emergence time of ADR, clinical manifestation, allergy history, dosage, prognosis and combined medication of the patients. It is useful to provide valuable references for rational use of these andrographolide injections in clinical practice.

Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

Ampelopsis grossedentata (Hand.-Mazz.) W.T. Wang has long been used as a traditional Chinese medicinal herb among the indigenous people in the Yangtze River region of China. Dihydromyricetin (DMY) is the most abundant (approximately 30%) and bioactive constituent in A. grossedentata (Hand.-Mazz.) W.T. Wang, and recent studies have demonstrated its various pharmacological activities. In the present study, a first specific, sensitive, rapid and reliable LC-MS/MS method for the determination of DMY in rat plasma was developed and validated. The plasma samples were prepared with protein precipitation method, and chromatographic separation was performed on a Welch Ultimate XB-C18 column (50 × 2.1 mm, 5 µm) using a gradient elution with water and acetonitrile. The mass spectrometry (MS) analysis was conducted in negative ionization mode with multiple reaction monitoring (MRM) transitions at m/z 319.1→192.8 for DMY and m/z 609.0→301.2 for rutin (IS). The plasma concentration profiles and pharmacokinetic parameters were analyzed after oral administration of dextroisomer and racemate DMY at the dose of 100 mg/kg in rats. The method validation was conducted over the calibration range of 10.0-5000 ng/ml with the intra- and inter-day precision and accuracy within 12.0% (RSD) and 5.6% (RE). The recoveries, matrix effect and stability under different conditions were all proved acceptable. The values of Tmax, AUC(0-∞) and Vd were significantly different between the groups of dextroisomer and racemate DMY (P<0.05), and pharmacokinetic results revealed their poor absorptions into blood, probably high tissue distributions and slow elimination processes. The present study will provide helpful information for the further studies and future clinical applications of DMY.