Efficacy and safety of high dose recombinant human thrombopoietin in the treatment of immune thrombocytopenia.

The conventional dose of recombinant human thrombopoietin (rhTPO) in the treatment of immune thrombocytopenia (ITP) is 300 U/kg per day, but the clinical reaction rate is not satisfactory. Accordingly, we explored the efficacy and safety of increasing rhTPO dose in the treatment of ITP. A retrospective study was conducted to collect the clinical data of 105 ITP patients who were divided into two groups, a low-dose group (15 000 U/day) and a high-dose group (30 000 U/day) according to the dose of rhTPO. The total effective rate of the low-dose group and the high-dose group was 31/44 (70.45%) vs. 56/61 (91.80%) (P = .049), and the average time of using rhTPO in the high-dose group was shorter than that in the low-dose group (7 days vs. 10 days, P = .001). On the 7th and 14th day of treatment, the efficacy of the high-dose group was better than that of the low-dose group [45/61 (73.77%) vs. 17/44 (38.64%), P < .001; 55/60 (91.67%) vs. 30/44 (68.18%), P < .05)]. The incidence of treatment related adverse events in the low-dose group and the high-dose group was 6/44 (13.64%) vs. 6/61 (9.84%) (P > .05), which were mild and transient in nature. In our study, high-dose rhTPO had good efficacy and high safety in the treatment of ITP with the efficacy better than low-dose rhTPO especially at day 7.

What is the context? Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by low platelet counts due to increased platelet destruction and impaired platelet production.The therapy direction of ITP involves promoting platelet generation, reducing excessive platelet destruction, immune regulation and so on.Recombinant human thrombopoietin (rhTPO), a promote platelet production drug, has pharmacological action similar to that of endogenous TPO. It can increase platelet count rapidly and effectively and has immunological regulation effect as well.It is found that rhTPO can rapidly and effectively increase platelet count, which has potential clinical application value in emergency situations.What is new? Traditionally, rhTPO has been recommended at 300 U/kg per day. Although it can greatly improve the treatment effect of ITP, the effect is not very satisfactory. In clinical practice, it has been observed that rhTPO dosage is often relatively insufficient and the therapeutic effect is poor. Therefore, we explored the efficacy and safety of increasing rhTPO dose in the treatment of ITP.Within the efficacy and safety of rhTPO 15 000 U/day and 30 000 U/day in the treatment of ITP, our analyses suggest that:The early response rate of the high-dose group was better than that of the low-dose group.In the high-dose group, the effective rate of rhTPO alone or combined with glucocorticoids was more than 90%.Treatment related adverse events occurred at a low rate and remained mild and transient.What is the impact? Comparing with conventional dose rhTPO, high-dose rhTPO may have better efficacy and safety in the treatment of immune thrombocytopenia and shorter administration time.

Effects of diet and gender on the pharmacokinetics of oral lenvatinib: A clinical trial in healthy Chinese participants.

OBJECTIVE: Lenvatinib is a tyrosine kinase inhibitor that helps prevent angiogenesis. In this study, we investigated the potential influencing factors on lenvatinib pharmacokinetics to provide a reference for clinical application. MATERIALS AND METHODS: All healthy participants received a single dose of 4 mg lenvatinib mesylate capsules with a high-fat meal or fasted conditions. Lenvatinib plasma concentrations were determined via high-performance liquid chromatography-mass spectrometry/mass spectrometry, and the pharmacokinetic parameters were calculated using WinNonlin 8.1 software. A mixed effect model analysis was adopted to explore the influence factor for the pharmacokinetic parameters of lenvatinib. RESULTS: After a single oral dose of 4 mg lenvatinib mesylate, the pharmacokinetic parameters for the fasted and fed groups were as follows: tmax was 2.0 hours and 4.5 hours, Cmax was 53.60 ng/mL and 45.54 ng/mL, AUC0-t was 597.44 h×ng/mL and 561.51 h×ng/mL, CL was 6.82 L/h and 7.26 L/h, and Vd was 82.82 L and 94.04 L, respectively. Compared with those in the fasted group, decreased Cmax and increased tmax were observed in the fed group. The geometric mean ratios of fed/fasted for Cmax, AUC0-t, and AUC0-∞ were 86.9%, 94.0%, and 93.9%, respectively, and the pharmacokinetics of lenvatinib were significantly influenced by food intake. Gender influenced the pharmacokinetics of lenvatinib; females had higher Cmax and AUC0-t levels after 4 mg lenvatinib. Lenvatinib was well tolerated in healthy Chinese subjects. CONCLUSION: High-fat diet altered the pharmacokinetic profile of lenvatinib, but not sufficient to significantly impact its clinical efficacy. Therefore, lenvatinib is suitable for administration under fasted or fed conditions.

Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of baloxavir in rat plasma and its application to pharmacokinetic studies.

In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method was established for the development and validation of baloxavir acid (BXA) concentrations and the active ingredients of the antiviral drug baloxavir marboxil (BXM). Further, the method was applied to study the pharmacokinetics of BXA. BXA was determined by the electrospray ionization multiple reaction monitoring positive ion mode, and the mass-to-charge ratios (m/z) of BXA and internal standard baloxavir-d4 were 484.2 → 247.2 and 488.1 → 247.2. An Oasis max online column (2.1 × 20 mm, 30 µm) was used with 1% formic acid in water (A) and 2% formic acid in acetonitrile (B) as mobile phases at a flow rate of 0.5 mL·min-1 for chromatographic separation. The linearity was good in the range of 3-200 ng·mL-1 (r = 0.9994), with 3.00 ng·mL-1 lower limit of quantification. The relative standard deviation of the inter-assay precision was less than or equal to 6.51%, and the accuracy was in the range of 91.28%-104.29%. This method is suitable for the determination of BXA and for performing pharmacokinetic studies in clinical research.

The Global Trend of Microplastic Research in Freshwater Ecosystems.

The study of microplastics and their impact on aquatic ecosystems has received increasing attention in recent years. Drawing from an analysis of 814 papers related to microplastics published between 2013 and 2022 in the Web of Science Core Repository, this paper explores trends, focal points, and national collaborations in freshwater microplastics research, providing valuable insights for future studies. The findings reveal three distinct stages of microplastics: nascent development (2013-2015), slow rise (2016-2018), and rapid development (2019-2022). Over time, the focus of research has shifted from "surface", "effect", "microplastic pollution", and "tributary" to "toxicity", "species", "organism", "threat", "risk", and "ingestion". While international cooperation has become more prevalent, the extent of collaboration remains limited, mostly concentrated among English-speaking countries or English and Spanish/Portuguese-speaking countries. Future research directions should encompass the bi-directional relationship between microplastics and watershed ecosystems, incorporating chemical and toxicological approaches. Long-term monitoring efforts are crucial to assessing the sustained impacts of microplastics.

HMBOX1, a member of the homeobox family: current research progress.

Homeobox containing 1 (HMBOX1) is a transcription factor that was identified in 2006 from a cDNA library of the human pancreas. It belongs to the HNF gene class of the homeobox family. HMBOX1 is widely expressed in normal human tissues; however, its expression level is rather uneven. Homeobox members have been widely reported to participate in embryonic development and differentiation as well as in pathological and physiological processes. Although research on the role of HMBOX1 is still in its infancy, many reports have revealed its regulatory role in cell differentiation, immune regulation, inflammation, and tumor progression. HMBOX1 plays an important role in promoting the differentiation of bone marrow stromal stem cells (BMSCs) into endothelial cells and contributes to their physiological functions. As an immunoregulatory factor, HMBOX1 can significantly inhibit the inflammatory response in hepatocytes and NK cells and impede the infiltration of peripheral immune cells to the liver. In tumor development, HMBOX1 exerts diametrically opposite biological functions, inhibiting or promoting the process. HMBOX1 possesses complex and diverse biological functions. In this review, we provide a brief overview of the research on HMBOX1.

Metabolomic analysis reveals the influence of HMBOX1 on RAW264.7 cells proliferation based on UPLC-MS/MS.

Macrophages are important effector cells in tumor progression and immune regulation. Previously, we demonstrated that the transcription suppressor homeobox containing 1(HMBOX1) exhibits immunosuppressive activity in LPS-induced acute liver injury by impeding macrophage infiltration and activation. We also observed a lower proliferation in HMBOX1-overexpressed RAW264.7 cells. However, the specific mechanism was unclear. Here, a work was performed to characterize HMBOX1 function related to cell proliferation from a metabolomics standpoint by comparing the metabolic profiles of HMBOX1-overexpressed RAW264.7 cells to those of the controls. Firstly, we assessed HMBOX1 anti-proliferation activity in RAW264.7 cells with CCK8 assay and clone formation. Then, we performed metabolomic analyses by ultra-liquid chromatography coupled with mass spectrometry to explore the potential mechanisms. Our results indicated that HMBOX1 inhibited the macrophage growth curve and clone formation ability. Metabolomic analyses showed significant changes in HMBOX1-overexpressed RAW264.7 metabolites. A total of 1312 metabolites were detected, and 185 differential metabolites were identified based on the criterion of OPLS-DA VIP > 1 and p value < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the elevated HMBOX1 in RAW264.7 inhibited the pathways of amino acid and nucleotide metabolism. Glutamine concentrations decreased significantly in HMBOX1-overexpressed macrophages, and glutamine-related transporter SLC1A5 was also downregulated. Furthermore, SLC1A5 overexpression reversed HMBOX1 inhibition of macrophage proliferation. This study demonstrated the potential mechanism of the HMBOX1/SLC1A5 pathway in cell proliferation by regulating glutamine transportation. The results may help provide a new direction for therapeutic interventions in macrophage-related inflammatory diseases.

Patients with von Willebrand disease in China: Results of an online survey.

INTRODUCTION: Little is known about the clinical characteristics of von Willebrand disease (VWD) patients in China, the impact of Covid-19 on them and their genetic mutation. AIM: To describe the clinical characteristics of a group of VWD patients in China, the impact of Covid-19 on them and their genetic mutation. METHODS: An online survey using a self-designed questionnaire was conducted among patients within a WeChat group of VWD patients in China. Data were analysed using t-test, the Chi-square test, Fisher's exact test and rank sum test. RESULTS: Data from a total of 96 patients were collected. Several important findings are yielded. Above all, type 3 patients accounted for over half of the surveyed patients. Secondly, a surprising rate (>40%) of patients had experience of being misdiagnosed. Thirdly, treatment regimens were dominated by cryoprecipitate, blood-derived FVIII and plasma, and only a small percentage of patients received prophylaxis. Fourthly, we identified 17 new von Willebrand factor (VWF) mutant genes which merit further investigation. Additionally, Covid-19 was found to pose some challenges for the patients. CONCLUSION: In China, the high rates of type 3 patients and misdiagnosis suggest that most of the VWD patients may never be diagnosed in China. When it comes to diagnosis and treatment, there is a large gap between developing countries like China and developed countries.

Prediction of janagliflozin pharmacokinetics in type 2 diabetes mellitus patients with liver cirrhosis or renal impairment using a physiologically based pharmacokinetic model.

Janagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). The janagliflozin pharmacokinetics (PK) in T2DM patients with cirrhosis or renal impairment (RI) are unknown. To predict the janagliflozin PK in these patients, we constructed a physiologically based PK (PBPK) model that predicted the janagliflozin PK in normal animals. The model was extrapolated to healthy humans and optimized with the measured data. A PBPK model for T2DM patients was developed and optimized with the measured data. Based on the physiological alterations in cirrhosis or RI patients, the T2DM model was applied to predict the janagliflozin PK in these patients. Results were validated using fold error values. The predicted AUC values were 21,880, 24,881, 26,996, and 28,419 ng/ml·h in T2DM patients with no cirrhosis, Child-Pugh-A, B, and C, respectively, and those in T2DM patients with RI-mild, RI-moderate, and RI-severe were 21,810, 21,840, and 22,845 ng/ml·h, respectively. Janagliflozin exposure increased with increasing cirrhosis severity, whereas it remained stable regardless of the RI severity. The PBPK model predicted the janagliflozin PK in patients with T2DM and liver cirrhosis or RI. Dose adjustment is less critical for these patients. Risk benefit assessment in janagliflozin dosing for T2DM patients with liver disease is recommended.

Effect of Food Intake on Pharmacokinetics of Oral Almonertinib: A Randomized Crossover Trial in Healthy Chinese Participants.

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) almonertinib (HS-10296) targets both EGFR-sensitizing and T790M resistance mutations. This randomized, open-label, two-period crossover trial investigated the effect of food intake on the single-dose pharmacokinetic properties of almonertinib and its metabolite HAS-719. Twenty healthy adults received a single dose of almonertinib tablets (110 mg) on days 1 and 22 under overnight fasting or fed conditions, respectively. Plasma samples were collected 216 hours post-dosing and almonertinib and HAS-719 concentrations were determined using liquid chromatography-tandem mass spectrometry. For almonertinib, the geometric mean ratio (GMR, fed/fasting) and 90% confidence interval (CI) for the area under the curve (AUC) from time 0 to 216 hours and apparent oral clearance (CLz /F) were 119.9 (110.0-130.7) and 83.5 (76.6-90.9), respectively. Fasting and fed groups showed significant differences in these parameters, but not for maximum concentration (Cmax ) and time to Cmax (Tmax ). The Cmax GMR of HAS-719 was 81.7 (75.8-88.0), which decreased significantly in the fed group. The drug-related adverse reaction (AR) incidence was similar in the two groups, 50% in the fasting group and 52.6% in the fed group. ARs were mainly gastrointestinal diseases and abnormal laboratory test results, and all participants fully recovered. In conclusion, a high-fat diet slightly affected the pharmacokinetic profile of almonertinib in healthy participants, but not the safety tolerance. Therefore, almonertinib is suitable for administration under fasting or fed conditions.

Levels of Soluble CD30 and CD26 and Their Clinical Significance in Patients with Primary Immune Thrombocytopenia.

BACKGROUND: sCD30 and sCD26 are correlated with autoimmune diseases. However, little research has been done on the relationship between them and primary immune thrombocytopenia (ITP). METHODS: This study enrolled 47 patients diagnosed with ITP in the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences (Tianjin, China), from January 2015 to August 2015. The peripheral blood of all subjects was collected. The mRNA expression of CD30 was quantified by RT-PCR, and concentrations of sCD30 and sCD26 were measured by ELISA. Patient characteristics, CD30 mRNA levels, and sCD30 and sCD26 concentrations were analyzed. RESULTS: The concentration of sCD30 was higher in active ITP patients (median, 35.82 ng/mL) than in remission ITP patients (median, 23.12 ng/mL; P = 0.021) and healthy controls (median, 25.11 ng/mL; P = 0.002). Plasma sCD26 levels decreased in remission ITP patients compared with that in healthy controls (median, 599.4 ng/mL vs. 964.23 ng/mL; P = 0.004). Ratios of sCD26/sCD30 in active ITP patients decreased compared with those in controls (P = 0.005). Increased sCD30 was positively correlated with hemorrhage (r = 0.493, P = 0.017) in ITP patients while little relationship was identified between sCD26 and ITP. CONCLUSION: Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.

Influence of soil and water conservation measures on soil fertility in the Beijing mountain area.

Soil and water conservation (SWC) measures can be adopted to conserve soil and water and improve soil fertility. The degree to which SWC measures improve soil fertility is affected by the type of SWC measure, soil type, climate, etc. The purpose of this study was to study the effect of the main SWC measures implemented in the Beijing mountain area on soil fertility. Six runoff plots, including a fish pit (fallow) (FPF), fish pit (Platycladus orientalis L. Franco) (FPP), narrow terrace (fallow) (NTF), narrow terrace (Juglans regia L.) (NTJ), tree pan (Juglans regia L.) (TPJ), and fallow land (FL), were established to analyze the differences in soil fertility in the Beijing mountain area. Soil samples were collected in 2005 and 2015 from the six runoff plots. Soil particle size; soil total nitrogen (TN), total phosphorous (TP), total potassium (TK), alkali-hydrolysable nitrogen (Ah-N), available P (Av-P), and available K (Av-K); and soil organic matter (SOM) were measured. The soil integrated fertility index (IFI) was calculated. The results showed that the soil nutrient content and IFI significantly decreased from 2005 to 2015 in the FL plot and significantly increased in the five runoff plots with SWC measures. Compared to the other runoff plots with SWC measures, the FPP plot more significantly improved the soil nutrient content and IFI. The TN, Ah-N, Av-K, SOM, and IFI in the FPP plots increased by 98%, 113%, 61%, 69 and 47%, respectively, from 2005 to 2015. The IFI for the FPP, NTJ, and TPJ exceeded the average IFI of the farmland soil in the study region. The results indicated that the combination of engineering practices and vegetative measures effectively improved soil fertility. These results may be helpful for selecting SWC measures, land-use planning and monitoring and assessing soil fertility.