OBJECTIVES: To evaluate the efficacy and safety of avatrombopag in promoting platelet engraftment after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children, compared with recombinant human thrombopoietin (rhTPO). METHODS: A retrospective analysis was conducted on 53 pediatric patients who underwent allo-HSCT at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from April 2023 to August 2024. Based on medications used during the periengraftment period, patients were divided into two groups: the avatrombopag group (n=15) and the rhTPO group (n=38). RESULTS: At days 14, 30, and 60 post-transplant, platelet engraftment was achieved in 20% (3/15), 60% (9/15), and 93% (14/15) of patients in the avatrombopag group, and in 39% (15/38), 82% (31/38), and 97% (37/38) in the rhTPO group, respectively. There were no significant differences between the two groups in platelet engraftment rates at each time point, cumulative incidence of platelet engraftment, overall survival, and relapse-free survival (all P>0.05). Multivariable Cox proportional hazards analysis indicated that acute graft-versus-host disease was an independent risk factor for delayed platelet engraftment (P=0.043). CONCLUSIONS In children undergoing allo-HSCT, avatrombopag effectively promotes platelet engraftment, with efficacy and safety comparable to rhTPO, and represents a viable therapeutic option.
Humans ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Male ; Female ; Child ; Child, Preschool ; Infant ; Adolescent ; Transplantation, Homologous ; Blood Platelets/drug effects* ; Thiazoles/therapeutic use* ; Thrombopoietin/therapeutic use* ; Thiophenes

OBJECTIVE: To investigate the safety and efficacy of avatrombopag（AVA） combined with rhIL-11 in treating thrombocytopenia induced by chemotherapy in acute myeloid leukemia. METHODS: The clinical information of 8 patients in the real world who received avatrombopag combined with rhIL-11 in cancer treatment-induced thrombocytopenia(CTIT) after AML chemotherapy were retrospectively analyzed, and at the same time, 8 patients who received rhIL-11 only in CTIT after AML chemotherapy served as the control group, A preliminary observation was to summarize and compare the therapeutic efficacy and adverse effects between the two groups. RESULTS: D3 and D7 platelet counts were not significantly different between the observation group and the control group after treatment. The platelet counts in the observation group was significantly higher than those of the control group on the 10th day after treatment (P < 0.01). The adverse reactions, such as weakness, abdominal pain, fatigue, nausea and edema after treatment were mild in the observation group and the control group. Except for one patient in the observation group who had a history of cerebral infarction before the onset of the disease and was routinely taking antiplatelet drugs, no thrombosis events occurred in the patients in the observation and control groups during the period of administration of the drug, and the total incidence rate of adverse reactions was not significantly different between the two groups. CONCLUSION The combination of AVA and rhIL-11 can enhance platelet recovery in CTIT of AML patients after chemotherapy. Compared with the rhIL-11 alone group, the platelet recovery time in AVA+rhIL-11 group was significantly shorter, the platelet count on the 10th day after drug administration was significantly higher. No statistically significant difference in the total incidence rate of adverse reactions was observed between rhIL-11 alone group and AVA+rhIL-11 group.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Thrombocytopenia/chemically induced* ; Interleukin-11/therapeutic use* ; Retrospective Studies ; Adult ; Thiophenes/therapeutic use* ; Platelet Count ; Female ; Male ; Middle Aged ; Thiazoles

BACKGROUND: Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT), and there is no standard therapy. Avatrombopag (AVA) is a second-generation thrombopoietin (TPO) receptor agonist (TPO-RA) that has shown efficacy in immune thrombocytopenia (ITP). However, few reports have focused on its efficacy in patients diagnosed with thrombocytopenia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We conducted a retrospective study at the First Affiliated Hospital of the University of Science and Technology of China to evaluate the efficacy of AVA as a first-line TPO-RA in 65 patients after UCBT; these patients were compared with 118 historical controls. Response rates, platelet counts, megakaryocyte counts in bone marrow, bleeding events, adverse events and survival rates were evaluated in this study. Platelet reconstitution differences were compared between different medication groups. Multivariable analysis was used to explore the independent beneficial factors for platelet implantation. RESULTS: Fifty-two patients were given AVA within 30 days post-UCBT, and the treatment was continued for more than 7 days to promote platelet engraftment (AVA group); the other 13 patients were given AVA for secondary failure of platelet recovery (SFPR group). The median time to platelet engraftment was shorter in the AVA group than in the historical control group (32.5 days vs . 38.0 days, Z  = 2.095, P  = 0.036). Among the 52 patients in the AVA group, 46 achieved an overall response (OR) (88.5%), and the cumulative incidence of OR was 91.9%. Patients treated with AVA only had a greater 60-day cumulative incidence of platelet engraftment than patients treated with recombinant human thrombopoietin (rhTPO) only or rhTPO combined with AVA (95.2% vs . 84.5% vs . 80.6%, P  <0.001). Patients suffering from SFPR had a slightly better cumulative incidence of OR (100%, P  = 0.104). Patients who initiated AVA treatment within 14 days post-UCBT had a better 60-day cumulative incidence of platelet engraftment than did those who received AVA after 14 days post-UCBT (96.6% vs . 73.9%, P  = 0.003). CONCLUSION Compared with those in the historical control group, our results indicate that AVA could effectively promote platelet engraftment and recovery after UCBT, especially when used in the early period (≤14 days post-UCBT).
Humans ; Female ; Male ; Thrombocytopenia/etiology* ; Adult ; Retrospective Studies ; Cord Blood Stem Cell Transplantation/adverse effects* ; Middle Aged ; Adolescent ; Young Adult ; Thiazoles/adverse effects* ; Platelet Count ; Receptors, Thrombopoietin/agonists* ; Child ; Thiophenes

Objective: To establish a high performance liquid chromatography method for the determination of 2-thioxothiazolidine-4-carboxylic acid (TTCA) in urine. Methods: After acidification with hydrochloric acid, TTCA in urine was first extracted by ethyl acetate with excessive sodium chloride, then gradient separated by a symmetry C18 column and then detected by a diode array detector. The quantification was based on a working curve of external standard method. Results: The linear relationship of TTCA in urine was good in the range of 0.03-10.00 mg/L, and the correlation coefficient was 0.9999. The detection limit and minimum quantitative concentration of TTCA in urine were 0.008 mg/L and 0.027 mg/L. The intra-assay precision of the method was 0.9%-1.4%, the inter-assay precision was 1.3%-3.5%, and the average recovery was 85.0%-92.7% while the concentrations of TTCA in urine was 0.8, 2.0 and 8.0 mg/L, respectively (n=6) . Conclusion: The gradient elution high performance liquid chromatography method has simple operation and high sensitivity, and it is suitable for the determination of TTCA on a low level in urine for occupational workers exposure to carbon disulfide.
Carbon Disulfide ; Chromatography, High Pressure Liquid/methods* ; Humans ; Thiazoles/urine* ; Thiazolidines ; Thiones

OBJECTIVE: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI). In current clinical situation, availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) has enabled physicians to switch among therapies owing to specific clinical scenarios. Although optimum time, loading dose and interval of transition between P2Y12 inhibitors is still controversial and needs further evidence, switching between oral inhibitors frequently occurs in clinical practice for several reasons. DATA SOURCES: This review was based on data in articles published in PubMed up to June 2018, with the following keywords "antiplatelet therapy", "ACS", "PCI", "ticagrelor", and "clopidogrel". STUDY SELECTION: Original articles and critical reviews on de-escalation strategy in ACS patients after PCI were selected. References of the retrieved articles were also screened to search for potentially relevant papers. RESULTS: Safety concerns associated with switching between antiplatelet agents, has prompted the use of clopidogrel for patients with ACS especially after PCI as a de-escalation strategy. Practical considerations for de-escalating therapies in patients with ACS such as reducing dose of P2Y12 inhibitors or shortening duration of DAPT (followed by aspirin or P2Y12 receptor inhibitor monotherapy) as potential options are yet to be standardized and validated. CONCLUSIONS Current review will provide an overview of the pharmacology of common P2Y12 inhibitors, definitions of de-escalation and different de-escalating strategies and its outcomes, along with possible direction to be explored in de-escalation.
Acute Coronary Syndrome ; drug therapy ; therapy ; Aspirin ; therapeutic use ; Diamines ; therapeutic use ; Humans ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors ; therapeutic use ; Purinergic P2Y Receptor Antagonists ; therapeutic use ; Thiazoles ; therapeutic use

PURPOSE: The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. MATERIALS AND METHODS: From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. RESULTS: Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. CONCLUSION: COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia.
Biliary Atresia/complications/enzymology/*surgery ; Child ; Child, Preschool ; Chronic Disease ; Cyclooxygenase 2 Inhibitors/*therapeutic use ; Female ; Humans ; Liver Cirrhosis/etiology/pathology/*prevention & control ; Male ; *Portoenterostomy, Hepatic ; Thiazines/*therapeutic use ; Thiazoles/*therapeutic use

Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.
Antiviral Agents ; chemistry ; Carrier Proteins ; chemistry ; Drug Resistance, Viral ; Endopeptidases ; Hepacivirus ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Oligopeptides ; chemistry ; Protease Inhibitors ; chemistry ; Serine Proteases ; Thiazoles ; chemistry ; Viral Nonstructural Proteins ; chemistry

OBJECTIVETo compare the clinical efficacy on knee osteoarthritis (KOA) at the early and middle stage between electroacupuncture (EA) and meloxicam.

METHODSNinety patients of KOA at the early and middle stage were randomized into an EA group and a meloxicam group, 45 cases in each one. In the EA group, EA was applied to Dubi (ST 35), Neixiyan (EX-LE 4), Liangqiu (ST 34), Heding (EX-LE 2), Xuehai (SP 10), Yan- glingquan (GB 34) and Zusanli (ST 36); the needles were retained for 20 min and EA was applied once every two days. In the meloxicam group, the meloxicam tablets were prescribed for oral administration, 7. 5 mg, once a day. The treatment lasted for 6 weeks in the two groups. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, rectus femoris muscle tension, the 8-foot walking test and 5-time sit-to-stand test were adopted to observe and compare the effects in the two groups.

RESULTSAfter treatment, every item score in WOMAC was reduced after treatment (all P < 0.05), but the difference was not significant between the two groups (all P > 0.05). In the EA group, the rectus femoris tension after treatment was reduced as compared with that before treatment (P < 0.05) and the reducing result was much more apparent as compared with that in the meloxicam group (P < 0.05). For the 8-foot walking test and 5-time sit-to-stand test, the time was shortened after treatment in the two groups (all P < 0.05) and the result in the EA group was much more obvious than that in the meloxicam group (both P < 0.05).

CONCLUSIONBoth EA and meloxicam are effective in the treatment of KOA at the early and middle stage. EA improves rectus femoris tension and recovers the internal mechanics balance and the efficacy is better than that of meloxicam.

Acupuncture Points ; Adult ; Aged ; Electroacupuncture ; Female ; Humans ; Male ; Middle Aged ; Osteoarthritis, Knee ; drug therapy ; therapy ; Thiazines ; therapeutic use ; Thiazoles ; therapeutic use ; Treatment Outcome

OBJECTIVE: To investigate the effects of LCL161, a Smac mimetic, on the proliferation and apoptosis in hepatocellular carcinoma cells and the underlying mechanisms. 
 METHODS: The effect of LCL161 on the cell viability of HepG2 and SMMC7721 cells was measured by MTT assay. The effect of LCL161 at lower concentrations on the proliferation in hepatocellular carcinoma (HCC) cells was detected by colony formation assay. Apoptosis was assessed by flow cytometry with PI staining. The mitochondrial membrane potential was measured by JC-1 staining. The expression of PARP, p-Akt, cIAP1 and XIAP protein was analyzed by Western blot.
 RESULTS: LCL161 displayed notable antiproliferative activity on HCC cells at the concentrations of 1-16 μmol/L (P<0.01), with IC50 values of 4.3 and 4.9 μmol/L for HepG2 and SMMC7721 cells, respectively, after treatment for 48 h. LCL161 at lower concentrations obviously inhibited the colony formation of HCC cells. LCL161 induced significant apoptosis in HCC cells (P<0.01), and resulted in the apoptotic rate at (1.5±0.8)% or (1.8±0.6)% , (15.2±2.8)% or (12.2±2.4)%, (28.7±3.0)% or (22.4±2.7)%, (34.6±2.3)% or (30.2±2.4)% for HepG2 cells or SMMC7721 cells at the concentration of 0, 2, 4 or 8 μmol/L, respectively. The result of JC-1 staining indicated that the mitochondrial membrane potential of HCC cells was reduced by LCL161. In addition, LCL161 promoted the cleavage of PARP, down-regulated the protein expression of p-Akt, and degraded cIAP1.
 CONCLUSION LCL161 possesses significant anti-proliferative activity and pro-apoptotic action in HepG2 and SMMC7721 cells, which might be correlated with reduction in mitochondrial membrane potential, down-regulation of p-Akt and degradation of cIAP1.
Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; drug therapy ; genetics ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; Down-Regulation ; Hep G2 Cells ; Humans ; Inhibitor of Apoptosis Proteins ; metabolism ; Liver Neoplasms ; Membrane Potential, Mitochondrial ; drug effects ; Proto-Oncogene Proteins c-akt ; genetics ; Thiazoles ; pharmacology ; Ubiquitin-Protein Ligases ; metabolism ; X-Linked Inhibitor of Apoptosis Protein

A lactoferrin-containing PEGylated liposome system (Lf-PLS) was developed and tested in vitro as a hepatoma-targeting drug delivery system. PEGylated liposomes (PLS) were successfully prepared using the thin film hydration method with peglipid post insertion. Lf was covalently conjugated onto the carboxyl terminal of DSPE-PEG2000-COOH on liposomes. Coumarin-6 was used to trace Lf-PLS with fluorescence. The cellular uptake of this system was carried out in asialoglycoprotein receptor (ASGPR) positive HepG2 cells via confocal microscopy and flow cytometry. The Lf-PLS liposome was observed as spherical or oval vesicles with the particle size around 130 nm, zeta potential about -30 mV and encapsulation efficiency more than 80%. The confocal microscopy images and flow cytometry data demonstrated that Lf-PLS resulted in significantly higher cell association by ASGPR positive HepG2 cells compared to PLS. The association between Lf-PLS and cells were dependent on the concentration, time and temperature, which was inhibited by pre-incubation with excessive free Lf. The results suggest that Lf-PLS has a good targeting effect on HepG2 cells in vitro. The targeting mechanism may be related to the specific binding of Lf and ASGPR on HepG2 cells, which guides Lf-PLS to the cell surface to induce an active endocytosis process. All these results demonstrated that Lf-PLS might be a potential drug delivery system in targeting hepatocellular carcinoma, which deserves more research on its targeting ability, antitumor efficiency, and metabolism in vivo for treatment of hepatomacellular carcinoma.
Asialoglycoprotein Receptor ; metabolism ; Carcinoma, Hepatocellular ; pathology ; Coumarins ; Drug Delivery Systems ; Endocytosis ; Hep G2 Cells ; drug effects ; Humans ; Lactoferrin ; pharmacology ; Liposomes ; Liver Neoplasms ; pathology ; Particle Size ; Phosphatidylethanolamines ; Polyethylene Glycols ; Thiazoles