Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.

Coronavirus disease 2019 (COVID-19) is now pandemic worldwide and has heavily overloaded hospitals in Wuhan City, China during the time between late January and February. We reported the clinical features and therapeutic characteristics of moderate COVID-19 cases in Wuhan that were treated via the integration of traditional Chinese medicine (TCM) and Western medicine. We collected electronic medical record (EMR) data, which included the full clinical profiles of patients, from a designated TCM hospital in Wuhan. The structured data of symptoms and drugs from admission notes were obtained through an information extraction process. Other key clinical entities were also confirmed and normalized to obtain information on the diagnosis, clinical treatments, laboratory tests, and outcomes of the patients. A total of 293 COVID-19 inpatient cases, including 207 moderate and 86 (29.3%) severe cases, were included in our research. Among these cases, 238 were discharged, 31 were transferred, and 24 (all severe cases) died in the hospital. Our COVID-19 cases involved elderly patients with advanced ages (57 years on average) and high comorbidity rates (61%). Our results reconfirmed several well-recognized risk factors, such as age, gender (male), and comorbidities, as well as provided novel laboratory indications (e.g., cholesterol) and TCM-specific phenotype markers (e.g., dull tongue) that were relevant to COVID-19 infections and prognosis. In addition to antiviral/antibiotics and standard supportive therapies, TCM herbal prescriptions incorporating 290 distinct herbs were used in 273 (93%) cases. The cases that received TCM treatment had lower death rates than those that did not receive TCM treatment (17/273 = 6.2% vs. 7/20= 35%, P = 0.0004 for all cases; 17/77= 22% vs. 7/9= 77.7%, P = 0.002 for severe cases). The TCM herbal prescriptions used for the treatment of COVID-19 infections mainly consisted of Pericarpium Citri Reticulatae, Radix Scutellariae, Rhizoma Pinellia, and their combinations, which reflected the practical TCM principles (e.g., clearing heat and dampening phlegm). Lastly, 59% of the patients received treatment, including antiviral, antibiotics, and Chinese patent medicine, before admission. This situation might have some effects on symptoms, such as fever and dry cough. By using EMR data, we described the clinical features and therapeutic characteristics of 293 COVID-19 cases treated via the integration of TCM herbal prescriptions and Western medicine. Clinical manifestations and treatments before admission and in the hospital were investigated. Our results preliminarily showed the potential effectiveness of TCM herbal prescriptions and their regularities in COVID-19 treatment.
Adult ; Aged ; Aged, 80 and over ; COVID-19/therapy* ; China ; Combined Modality Therapy ; Drugs, Chinese Herbal/therapeutic use* ; Female ; Hospitalization ; Humans ; Male ; Medicine, Chinese Traditional ; Middle Aged ; Retrospective Studies ; Survival Rate ; Treatment Outcome

Objective To assess the feasibility,safety and efficacy of endoscopic papillectomy (EP) for tumors at the ampulla of Vater (AV).Methods A total of 15 patients with tumor at AV that were indicated for EP were included in this prospective study.Their clinical profiles,procedural parameters and outcome were evaluated.Results All patients underwent EP procedure successfully.Four patients who were diagnosed as having chronic inflammation in the reference endoscopy were confirmed as having adenoma after EP.Out of the 11 patients who were previously diagnosed as andenoma on biopsy,2 of low differentiated adenocarcinoma,1 of well differentiated adenocarcinoma and 1 malignant transformation were pathologically confirmed after EP.Stents were implanted in 8 patients with dilated pancreatic and/or common bile duct.Except for 2 cases of melena and 2 transient elevated level of blood amylase after EP,no other major complications occurred.Three patients,including 1 case of low-differentiated adenocarcinoma,1 case of malignant transformation and 1 case of lesion residual,were referred to surgery,another patient with low-differentiated adenocarcinoma declined any additional intervention because of old age.In the remaining 11 cases ( 11/15,73.3％ ) including one well differentiated adenocarcinoma,no recurrence was observed during a follow-up period of 23.4 (5 to 47) months.Conclusion EP is a minimal invasive,safe and effective treatment for tumors at AV,which also can provide an accurate staging of the lesion.

OBJECTIVETo study the pharmacokinetics of single administration and different compatibility of tetramethylpyrazine (TMP) in rats.

METHODThirty two Sprague-Dawley rats were randomly divided into 4 groups: the TMP (30 mg x kg(-1)) group, the TMP+FA (30 mg x kg(-1) + 50 mg x kg(-1)) group, the TMP+TET (30 mg x kg(-1) mg x kg(-1)) group and the TMP+FA+TET (30 mg x kg(-1) + 50 mg x kg(-1) + 20 mg x kg(-1)) group. After the oral administration, their blood samples were collected to detect plasmas concentrations by HPLC method and to calculate pharmacokinetic parameters DAS 2.0 program.

RESULTIn compatibility with FA, AUC(0-t), Cmax and Tmax showed no significant difference with the single administration of TMP, but t(1/2) and MRT,, were obviously longer than the single administration. In compatibility with TET and FA + TET, AUC (0-t), Cmax and Tmax showed significant increase than the single administration of TMP, whereas t(1/2) and MRT0, did not notably vary from the single administration.

CONCLUSIONFA can prolong TMP's action time in rats, and TET can accelerate TMP's absorption in rats.

Animals ; Chromatography, High Pressure Liquid ; Coumaric Acids ; pharmacokinetics ; Diterpenes ; pharmacokinetics ; Drug Interactions ; Female ; Pyrazines ; pharmacokinetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley

In this paper, the pharmacokinetics of ferulic acid loaded liposome-in-chitosan-microspheres was investigated. Eighteen Sprague-Dawley rats were divided into 3 groups randomly. Each group was administered orally of ferulic acid, ferulic acid loaded chitosan microspheres and ferulic acid loaded liposome-in-chitosan-microspheres, respectively. Then blood samples were obtained from fossa orbitalis at different time points. The concentration of ferulic acid in blood was analyzed by a HPLC method using coumarin as internal standard. The data were analyzed by DAS program. The t(max), MRT and t(1/2beta) of liposome-in-chitosan-microspheres were 2.500, 7.487 and 7.818 h, respectively, which were much longer than crude drug and chitosan microspheres. This results demonstrated that liposome-in-chitosan-microspheres had better sus-tained-releasing property. The AUC of liposome-in-chitosan-microspheres was 6.08 times higher than crude drug and 1.21 times higher than chitosan microspheres, which verified that liposome-in-chitosan-microspheres could enhance oral absorption.
Absorption ; Administration, Oral ; Animals ; Anticoagulants ; administration & dosage ; blood ; pharmacokinetics ; Biocompatible Materials ; Chitosan ; Coumaric Acids ; administration & dosage ; blood ; pharmacokinetics ; Delayed-Action Preparations ; Liposomes ; Male ; Microspheres ; Orbit ; blood supply ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Time Factors

ObjectiveTo observe the treatment effects in 48 cases of advanced lung cancer patients,with the immune therapy of the dendritic cells loading of tumor autologous antigen (DCTAA) combining with the cells induced factor of the killer cells(CIK)from the matched umbilical cord blood cells.MethodsThe peripheral blood mononuclear cell(PBMC)from the matched umbilical cord blood cells was seperated,and induced to CIK and DC with some cytokines in vitro, such as CD3McAb, IL-2, IFN-γ IL-1α, etc. After 12 to 15 days, the amplified CIK cells obtained were obtained, with the strict quality control, infused the CIK cells to the patients body back in six times,about(5-8)×109 CIK cells in each time.In the fifth day of the cultivation,DETAA cells were loaded and DCTAA cells were collected in the eighth day,and then hypodermic injection was done. The patient' s general situation after the immune treatment was observed, such as the size of the tumors, clinical symptom score, the quality of life and immune indexes. Karnofsky score, weight, toxic side effects and the patient's survival were also studied.ResultsIn the 48 cases with the DCTAA-CIK treatment, complete remission (CR), partial remission (PR)was 37 cases, the overall remission rate was 77.1％. The improvement rate of clinical symptom scores was from 78.9 ％ to 84.7 ％, the increasing rate of Karnofsky score was 89.6 ％ (43/48). 1-year survival reached to 80.6 ％. There were significant difference in little toxic side effects(P ＜ 0.01). The proportion of CD3, CD4 and NK cells in peripheral blood cells increased significantly (P ＜ 0.01) after DCTAA-CIK cells treatment[(42.21±6.12)％, (24.42±3.01)％, 0.99±0.34, (24.98±3.02) ％; (71.58±7.64) ％, (37.25±2.13) ％, 1.62±0.45, (35.23±4.11) ％](t = 6.34, 5.67, 0.25, 4.43, P ＜0.01).ConclusionThe DCTAA-CIK immune therapy is benefit for advanced lung cancer,not only improve the immune function but also ameliorate the clinical symptoms.

OBJECTIVETo construct the ferulic acid loaded chitosan microspheres containing liposomes.

METHODFerulic acid was selected to be the model drug. Liposomes were prepared by calcium acetate gradient method. The entrapment efficiency of liposomes was(79.97 +/- 0.54)%, the average size was (187.6 +/- 11.9) nm and the Zeta potential was -12.67 +/-1.78. The chitosan microspheres, whose entrapment efficiency was (57.89 +/- 1.72)%, were prepared by onic gelation method after liposomes were mixed with chiotosan solution. Ferulic acid was entrapped in liposomes in amorphous form and then liposomes were distributed in microspheres intactly.

RESULTThe 80.97% liposomes were released from microspheres and the 32.33% ferulic acid was released from microspheres at 12 h, which was much slower than simple chitosan microspheres.

CONCLUSIONThis study demonstrated that chitosan microspheres containing liposomes have good sustained-releasing property in vitro.

Chemistry, Pharmaceutical ; Chitosan ; chemistry ; Coumaric Acids ; chemistry ; pharmacokinetics ; Delayed-Action Preparations ; chemistry ; pharmacokinetics ; Drug Compounding ; Kinetics ; Liposomes ; chemistry ; Microspheres ; Particle Size

OBJECTIVETo study the pharmacokinetics of tetramethylpyrazine (TMP), ferulic acid and their compatibility.

METHODTwenty-four Sprague-Dawley rats were randomly divided into 3 groups: TMP 20 mg x kg(-1), ferulic acid 20 mg x kg(-1) and TMP 20 mg x kg(-1) + ferulic acid 20 mg x kg(-1). All the rats were given intragastric administration then blood samples were obtained from fossa orbitalis at several time points. All the plasmas concentrations were analyzed by HPLC method and the data were treated by DAS 2.0 program.

RESULTThe main pharmacokinetics parameters of TMP 20 mg x kg(-1) group, ferulic acid 20 mg x kg(-1) and TMP 20 mg x kg(-1) + ferulic acid 20 mg x kg(-1) were as follows: t(max) 0.5 h, t1/2 0.856 h,MRT 1.321 h, AUC 5.112 microg x h(-1) x L(-1), C(max) 2.834 microg x L(-1); t(max) 0.083 h, t1/2 1.024 h, MRT 1.324 h, AUC 1.581 microg x h(-1) x L(-1), C(max) 1.492 microg x L(-1); t(max) 0.583 h, t1/2 37.901 h, MRT 3.798 h, AUC 4.097 microg x h(-1) x L(-1), C(max)1.571 microg x L(-1); t(max) 0.6 h, t1/2 7.860 h, MRT 2.894 h, AUC 1.984 microg x h(-1) x L(-1), C(max) 1.03 microg x L(-1), respectively.

CONCLUSIONThe experiments suggested that the compatibility of TMP and ferulic acid had interaction in pharmacokinetics; all the t1/2 and MRT were prolonged and had the effect of lente liberates.

Animals ; Area Under Curve ; Calibration ; Coumaric Acids ; pharmacokinetics ; Female ; Linear Models ; Pyrazines ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results

OBJECTIVETo explore the effect of tetramethylpyrazine (TMP) on the expression of vascular endothelial growth factor (VEGF) in the synovium of adjuvant-induced arthritis (AIA) in rats.

METHODAIA rats were treated with different doses of TMP. The effects of treatment were monitored by footpad thickness, contents of tumor necrosis factor-alpha (TNF-alpha) in serum, microvessel density (MVD) and the expression of VEGF protein in the synovium.

RESULTCompared with arthritis model, 100 mg x kg(-1) TMP could remarkably reduce the footpad thickness, contents of TNF-alpha in serum and the expression of VEGF in the synovium.

CONCLUSIONTMP can attenuate the degree of chronic inflammation in AIA rats, and its mechanism might be associated with inhibiting the expression of VEGF.

Animals ; Arthritis, Experimental ; drug therapy ; genetics ; metabolism ; Disease Models, Animal ; Gene Expression ; drug effects ; Humans ; Male ; Pyrazines ; therapeutic use ; Rats ; Rats, Wistar ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

The valaciclovir was used as the model drug, the bovine serum albumin nanoparticles (BSA-NP) were prepared by desolvation process. Glycyrrhizin (GL) was oxidized by sodium periodate to be conjugated to surface reactive amino groups (SRAG) of the VACV-BSA-NP. Gel filtration method combined with HPLC method verified that GL was covalent coupling to the surface of VACV-BSA-NP with mean 9 GL residues per albumin molecule. The mean diameter of the VACV-BSA-NP-GL was 268 +/- 23 nm, the drug loading was 1.35%, and embedding ratio was 68.76%. The characteristics of release in vitro were in accord with two-phase kinetics. The uptake amount of VACV-BSA-NP-GL by primary cultured rat hepatocytes in vitro was higher, compared to the control-VACV-BSA-NP. 69.89% and 64.82% of the VACV were concentrated in liver at 15 min after i.v. VACV-BSA-NP-GL and VACV-BSA-NP, respectively. There is a significant difference between surface-modified group and control group (P<0.10). VACV-BSA-NP-GL was successfully prepared, which is considered to be a novel drug delivery system for targeting to hepatocytes.
Acyclovir ; analogs & derivatives ; pharmacology ; Cells, Cultured ; Drug Delivery Systems ; Glycyrrhizic Acid ; pharmacology ; Hepatocytes ; cytology ; metabolism ; Humans ; Microspheres ; Nanostructures ; Nanotechnology ; Particle Size ; Serum Albumin, Bovine ; pharmacology ; Technology, Pharmaceutical ; methods ; Valine ; analogs & derivatives ; pharmacology