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Gender heterogeneity in the influencing factors for cerebral microbleeds in acute ischemic stroke patients.
Guo, X, Xing, Y, Teng, Z, Shen, Z, Guo, X, Lv, P, Tian, S
Current medical research and opinion. 2023;(7):1045-1054
Abstract
BACKGROUND Cerebral microbleeds (CMBs) are common in acute ischemic stroke (AIS) patients. The presence of CMBs increases the risk of hemorrhagic transformation in AIS patients, and it is also closely associated with cognitive decline and even dementia. At present, there exist different opinions on the independent risk factors for CMBs, and there is no consensus on whether there are gender differences in -post-stroke CMB. Therefore, this study sought to investigate gender heterogeneity in the influencing factors for CMBs by studying male and female AIS patients. METHODS This was a China-based, Single-center, retrospective review of data from 482 AIS inpatients at the Neurology Department of Hebei General Hospital (NCT05882123). Both demographic and clinical data were collected from the study subjects. Different head magnetic resonance imaging sequences were used to assess the subjects' CMBs, white matter lesions, and old lacunar infarcts (LI). Various statistical methods, including the t-test, χ2 test, and logistic regression, were used to analyze the gender heterogeneity of the influencing factors for CMBs in AIS patients. RESULTS When compared with the male AIS patients, the female AIS patients were older and had higher total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, ApoA, ApoB, and fibrinogen levels. The female AIS patients also had higher National Institute of Health Stroke Scale scores and hypertension disease composition ratios. By contrast, the proportions of female AIS patients with a history of smoking and a history of alcohol consumption were both lower than the corresponding proportions of male AIS patients. These differences were all statistically significant (p < .05). There were no statistically significant differences in the incidence and severity of CMBs between the male and female AIS patients (χ2 = 0.851, 3.092, p > .05). The univariate and multivariate stepwise logistic regression analyses confirmed that age (OR = 1.074, 95% CI: 1.013-1.139, p = .016) and old LI (OR = 4.295, 95% CI: 1.062-17.375, p = .041) were independent risk factors for comorbid CMBs in the female AIS patients, while blood glucose (OR = 0.692, 95% CI: 0.494-0.968, p = .031) was an independent protective factor for comorbid CMBs in the female AIS patients. However, these factors were not found to be independent risk or protective factors for comorbid CMBs in male AIS patients. CONCLUSION There are gender differences in the influencing factors for CMBs in AIS patients. Age, old LIs, and blood glucose are independent risk or protective factors for comorbid CMBs in female AIS patients, although they are not associated with the risk of developing CMBs in male AIS patients.
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Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.
Lin, Y, Qin, S, Yang, H, Shi, F, Yang, A, Han, X, Liu, B, Li, Z, Ji, Q, Tang, L, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(15):2791-2799
Abstract
PURPOSE The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
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The Clinical and Molecular Characteristics of FLT3 Mutations in Chinese De Novo Adolescent and Adult Acute Lymphoblastic Leukemia Patients.
Shen, Z, Chu, XL, Wang, RX, Li, JL, Liu, MY, Xie, YY, Wang, C, Han, R, Yu, JQ, Wang, J, et al
Clinical lymphoma, myeloma & leukemia. 2020;(6):e259-e269
Abstract
BACKGROUND Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are frequent in acute myeloid leukemia (AML) and have important prognostic and therapeutic implications. FLT3 aberrations have been detected in a smaller fraction of acute lymphoblastic leukemia (ALL), and their prognostic value is not well established. We therefore assessed the FLT3 mutation in Chinese adolescent and adult ALL patients. PATIENTS AND METHODS We have examined a cohort of 117 Chinese de novo adolescent and adult ALL patients enrolled between June 2016 and June 2017 from the First Affiliated Hospital of Soochow University. Prognostic factors for the ALL patient population were estimated by the Cox regression method. FLT3 mutation was detected by PCR, and its clinical effect was assessed by Kaplan-Meier curves. Differences in FLT3 mutation rate between subgroups were tested by chi-square test. RESULTS FLT3 mutations accounted for 6.8% (8/117) in our cohort, including 3 internal tandem duplications (2.6%) and 5 tyrosine kinase domains (4.3%, 3 D835Y mutations, 1 M664I mutation, and 1 I867S mutation), which had no clinical significance on either overall survival (OS) or event-free survival. Alterations in FLT3 occurred more often in early thymic precursor (ETP)-ALL compared to non-ETP T-cell acute lymphoblastic leukemia (P = .028). However, the age at onset (P = .004), initial platelet counts (P = .018), and transplantation status (P = .007) were independent prognostic factors of OS for ALL in multivariate analysis. CONCLUSION The FLT3 mutation was not common in Chinese ALL patients. Age at onset, platelet counts, and transplantation status rather than the presence of the FLT3 mutation were independent prognostic variables for ALL on OS in our cohort. Despite our small sample size, ETP-ALL may indicate a comparable higher FLT3-mutant rate. Because ETP-ALL has been identified as high-risk subgroup, these data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic hematopoietic stem-cell transplantation for FLT3-mutant ETP-ALL.
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Characterization of Stereoselective Metabolism, Inhibitory Effect on Uric Acid Uptake Transporters, and Pharmacokinetics of Lesinurad Atropisomers.
Yang, C, Zhou, D, Shen, Z, Wilson, DM, Renner, M, Miner, JN, Girardet, JL, Lee, CA
Drug metabolism and disposition: the biological fate of chemicals. 2019;(2):104-113
Abstract
Lesinurad [Zurampic; 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)], a selective inhibitor of uric acid reabsorption transporters approved for the treatment of gout, is a racemate of two atropisomers. The objective of this investigation was to evaluate the stereoselectivity of metabolism, the inhibitory potency on kidney uric acid reabsorption transporters (URAT1 and OAT4), and the clinical pharmacokinetics of the lesinurad atropisomers. Incubations with human liver microsomes (HLM), recombinant CYP2C9, and recombinant CYP3A4 were carried out to characterize the stereoselective formation of three metabolites: M3 (hydroxylation), M4 (a dihydrodiol metabolite), and M6 (S-dealkylation). The formation of M3 in HLM with atropisomer 1 was approximately twice as much as that with atropisomer 2, whereas formation of M4 with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy human volunteers, the systemic exposure (C max at steady state and area under the concentration-time curve from time zero to the time of dosing interval) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 stable cells expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1.
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5.
Lesinurad: Evaluation of Pharmacokinetic and Pharmacodynamic Interactions With Warfarin in Healthy Volunteers.
Shen, Z, Lee, CA, Wallach, K, Valdez, S, Wilson, DM, Kerr, B, Gillen, M
Clinical pharmacology in drug development. 2019;(5):657-663
Abstract
Lesinurad is a selective uric acid reabsorption inhibitor approved for use in combination with xanthine oxidase inhibitors for the treatment of hyperuricemia associated with gout. In vitro, lesinurad was shown to be a weak inhibitor of cytochrome P450 (CYP)2C9 and a weak inducer of CYP3A4. Warfarin is a widely prescribed oral coumarin-based anticoagulant commonly prescribed in gout patients. In an open-label clinical study in healthy adult male subjects, the effects of multiple daily doses of 400 mg lesinurad on the pharmacokinetics and pharmacodynamics of a single dose of 25 mg warfarin (racemic mixture of R- and S- enantiomers) were evaluated. Lesinurad had no effect on the absorption or the exposure (area under the concentration-time curve [AUC] and peak concentration) of the more active S-warfarin enantiomer. A slight reduction (19%) in overall plasma exposure (AUC) was observed for the R-warfarin enantiomer. Lesinurad had no meaningful clinical impact on anticoagulation activity as measured by prothrombin time, activated partial thromboplastin time, and international normalized ratio of prothrombin time and Factor VII clotting activity. Overall, the administration of warfarin in the presence of multiple-dose lesinurad was devoid of clinically significant drug-drug interaction.