Cardiovascular toxicities following the use of tyrosine kinase inhibitors in hepatocellular cancer patients: a retrospective, pharmacovigilance study.

BACKGROUND: Cardiac adverse events (AEs) are common in tyrosine kinase inhibitors(TKIs). This study explored the cardiac AEs of TKIs through the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected cardiac AEs of TKIs, based on FAERS data from January 2004 to December 2021. RESULTS: A total of 4708 cardiac AEs reports of sorafenib, regorafenib, lenvatinib, and cabozantinib were identified. Hypertension accounts for the most reported cardiac AE. Lenvatinib appears to induce cardiac failure with the highest signals strength [ROR = 7.7 (3.46,17.17)]. Acute myocardial infarction was detected in lenvatinib [ROR = 7.91 (5.64,11.09)] and sorafenib [ROR = 2.22 (1.74, 2.84)]. Acute coronary syndrome was detected in lenvatinib [ROR = 11.57 (6.84, 19.58)] and sorafenib [ROR = 2.81 (1.87,4.24)]. Atrial fibrillation was detected in sorafenib [ROR = 1.82 (1.55,2.14)] and regorafenib [ROR = 1.36 (1.03,1.81)]. Meanwhile, aortic dissections were detected in sorafenib [ROR = 5.08 (3.31,7.8)] and regorafenib [ROR = 3.39 (1.52,7.56)]. Most patients developed hypertension and cardiac failure within 30 days of initiating TKI treatments. Patients taking lenvatinib had an increased incidence of developing acute coronary syndrome after 180 days of treatment. CONCLUSION: Analysis of FAERS data provides a precise profile on the characteristics of cardiac AEs associated with different TKI regimens. Distinct monitoring and appropriate management are needed in the care of TKI recipients.

[Mechanisms of Astragalus Polysaccharids Synergized with Doxorubicin against Drug Resistance in HL-60/A Cells].

OBJECTIVE: To explore the synergistic anti-tumor mechanism of astragalus polysaccharids(APS) combined with doxorubicin in HL-60/A cells. METHODS: The phenotype of HL-60/A was identified by using RT-PCR, Wester blot and CCK-8, the antitumor effect of astragalus polysaccharids combined with doxorubicin on HL-60/A cells was detected by CCK-8, the apoptosis of HL-60/A after treating with different drugs was detected by Annexin-V, the caspase casade activation was detected by Wester blot, the effect of astragalus polysaccharids on expression and function of multidrug resistance protein (MRP) was detected by using real-time quantitative PCR and Western blot. RESULTS: HL-60/A cells displayed obvious characteristics of resistance to doxorubicin, whose resistance were about 27 times that of its sensitive cell line HL-60. In addition, it was further found that astragalus polysaccharids could obviously increase the cell growth inhibition, induce cell apoptosis and caspase cascade activation, decrease the expression of MRP and increase the drug concentration in HL-60/A when combined with doxorubicin. CONCLUSION: Astragalus polysaccharids combined with doxorubicin can effectively overcome the drug resistance of HL-60/A. The mechanism may be associated with decreasing the expression of MRP, inhibiting drug efflux and increasing the intracellular drug concentration, then inducing HL-60/A cell apoptosis.

[OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 µmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) µmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 µmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence.

Is Urgent Decompression Superior to Delayed Surgery for Traumatic Spinal Cord Injury? A Meta-Analysis.

BACKGROUND: Traumatic spinal cord injury (SCI) is a common disease in current clinical practice. Previous studies have reported that early surgical decompression was better to improve neurologic outcomes than that of late surgery. However, most of the studies set early surgery within 72 hours. Is urgent surgery within 24 hours superior to late surgery for SCI? It remains controversial. OBJECTIVE: To determine whether neurologic outcomes of SCI in patients who underwent early surgery (<24 hours after injury) are better than those who underwent late surgery (≥ 24 hours after injury) by meta-analysis. METHODS: Electronic databases such as PubMed, MEDLINE, EMBASE, and Cochrane library were selected to detect the potentially related trials up to June 2015 that compared the outcomes of early surgery (<24 hours after injury) versus late surgery (≥ 24 hours after injury) for the treatment of traumatic SCI. Data extraction and quality assessment were according to Cochrane Collaboration guidelines. Outcome evaluations were total motor score, neurologic improvement rate, length of hospital stay and intensive care unit (ICU) stay, complications, and mortality. Results were expressed as odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence interval (CI). RESULTS: Nine articles comparing 2 cohorts that had early and late surgery for SCI were identified in this study. Statistically, there were significant differences between early and late surgery in total motor score (MD = 3.30, 95% CI = 0.82 ∼ 5.79, P < 0.01), neurologic improvement rate (OR = 1.66, 95% CI = 1.19 ∼ 2.31, P < 0.01), length of hospital stay (MD = -4.76, 95% CI = -9.19 ∼ -0.32, P = 0.04), and complications (OR = 0.61, 95% CI = 0.40 ∼ 0.91, P = 0.02). However, no significant differences were found between the 2 groups in mortality (OR = 1.39, 95% CI = 0.51 ∼ 3.75, P = 0.52). Two studies showed fewer ICU stays in the early-surgery group than in the late group. CONCLUSIONS: On the basis of this meta-analysis, urgent surgery within 24 hours for SCI significantly improved the neurologic outcomes compared with late surgery. It is suggested that urgent decompression within 24 hours is superior to delayed surgery for SCI.

Hybrid Decompression Technique Versus Anterior Cervical Corpectomy and Fusion for Treating Multilevel Cervical Spondylotic Myelopathy: Which One Is Better?

BACKGROUND: The hybrid decompression technique (corpectomy combined with discectomy) and anterior cervical corpectomy with fusion (ACCF) both provide good neurological recovery and disease stabilization for the treatment of multilevel cervical spondylotic myelopathy (CSM). However, no single study has been large enough to determine definitively which one is superior for this condition. OBJECTIVE: A meta-analysis was conducted to compare the clinical efficacy and safety of the hybrid decompression technique versus ACCF for the treatment of multilevel CSM. METHODS: Electronic databases such as PubMed, MEDLINE, EMBASE, Google Scholar, and the Cochrane Library were selected to search for potentially relevant trials up to April 2015 that compared the outcomes of the hybrid technique with ACCF for the treatment of multilevel CSM. Data extraction and quality assessment were performed according to Cochrane Collaboration guidelines. The outcome assessments were duration of surgery, blood loss, Cobb angle of C2-C7, segment angle, fusion rate, Japanese Orthopedics Association score, Neck Disability Index, and complications. The results were expressed as the odds ratio (OR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes with a 95% confidence interval (CI). RESULTS: Five controlled clinical trials published between 2009 and 2013, involving 356 patients (hybrid, 196; ACCF, 160) with 3- or 4-level CSM were retrieved in this study. Overall, there were significant differences between the 2 treatment groups for blood loss (MD = -38.69, 95% CI = -54.62 to -22.76, P < 0.01), fusion rate (OR = 2.56, 95% CI = 1.11 to 5.93, P = 0.03), and complications (OR = 0.25, 95% CI = 0.15 to 0.43, P < 0.01). However, no significant differences were found for duration of surgery (MD = -4.50, 95% CI = -22.902 to 13.91, P = 0.63), Cobb angle of C2-C7 after surgery (MD = 3.32, 95% CI = -3.72 to 10.37, P = 0.35), segment angle after surgery (MD = 2.87, 95% CI = -2.47 to 8.21, P = 0.29), Japanese Orthopedics Association score (MD = -0.07, 95% CI = -0.36 to 0.22, P = 0.62), or Neck Disability Index (MD = -0.86, 95% CI = -3.26 to 1.54, P = 0.48). CONCLUSION: Based on this meta-analysis, both the hybrid technique and ACCF can achieve good results for CSM. However, the hybrid technique is associated with significantly less blood loss, complications, and a higher fusion rate than ACCF.

Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro.

OBJECTIVE: To evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro. METHODS: Firstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells. RESULTS: As a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. CONCLUSION: Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.

Gene therapy in B-NHL cell line using adenovirus-mediated transfer of secretable trimeric TRAIL gene expression driven by CD20 promoter.

CD20 is a crucial target to B-non-Hodgkin lymphoma (NHL), in fact, a humanized anti-CD20 monoclonal antibody, rituximab, is widely applied in clinical practice. However, resistance to rituximab often occurs in B-NHL patients, which has encouraged us to find new medications to treat B-NHL. In this study, we designed a gene therapy strategy targeting CD20 at a transcriptional level mediated by adenovirus, in which the stTRAIL gene was driven by a specific CD20 promoter fragment. We cloned the CD20 promoter from genome DNA of BJAB cell, a CD20-positive cell line, and identified its specific transcriptional activity with a dual-luciferase reporter assay system. Meanwhile, we constructed the stTRAIL gene sequence, which contained secretion signal, isoleucine zipper, and soluble TRAIL gene sequence, in which the isoleucine zipper facilitated the product of this gene sequence to form a functional homotrimer. The recombinant adenovirus was termed as AdP20-stTRAIL, which carried on the fused gene of the CD20 promoter fragment and the stTRAIL gene. Our studies confirmed that the stTRAIL could be expressed and secreted from BJAB cells infected with AdP20-stTRAIL specifically, and it inhibited the growth of these infected BJAB cells in vitro and in vivo. Our results indicate that the gene therapy using stTRAIL gene driven by a CD20 promoter may be an effective strategy in B-NHL treatment.

[The cytotoxicity of indirubin derivative PHII-7 against human breast cancer MCF-7 cells and its mechanisms].

OBJECTIVE: To observe the cytotoxicity of indirubin derivative PHII-7 against human breast cancer MCF-7 cells and to study its primary mechanisms. METHODS: The proliferation of MCF-7 cells was detected using MTT colorimetry. Annexin V/PI double staining was applied to detect the apoptosis rate of MCF-7 cells. The distribution of cell cycles was detected using PI staining and flow cytometry (FCM). The levels of reactive oxygen species (ROS) in MCF-7 cells were detected by DCFH-DA staining. The mRNA and protein levels of c-fos were detected using RT-PCR and Westem blot analysis. RESULTS: PHII-7 at different concentrations inhibited the proliferation of MCF-7 cells in a concentration-dependent manner, with the inhibitory rate ranging from 43.13% to 90.90% (P < 0.05). The inhibition was strengthened along with increased concentrations. PHII-7 at different concentrations could induce the apoptosis of MCF-7 cells. The early apoptosis rate was 1.43% +/- 0.02%, 9.14% +/- 0.36%, and 45.79% +/- 8.46%, respectively with the action of 1.25, 2.50, and 5.00 micromol/L PHII-7, respectively, showing dose-dependent manner. FCM analysis found that the proportion of MCF-7 cells in the G0/G1 phase and the S phase decreased after treatment with PHII-7, and the ratio of MCF-7 cells in the G2/M phase obviously increased (P < 0.01). The intra-cellular ROS level was significantly elevated 2 h after pretreatment with PHII-7. The levels of the protooncogene c-fos mRNA and protein were down-regulated in a dose-dependent manner after action of PHII-7. CONCLUSIONS: PHII-7 exerted obvious in vitro cytotoxic effects on MCF-7 cells. Its mechanisms might be associated with arresting the cell cycle, regulating the redox equilibrium, and down-regulating the expression of the protooncogene.

[Effects of rhBNP on left ventricular remodeling in rats with acute myocardial infarction].

OBJECTIVE: To assess the effects of rhBNP on left ventricular (LV) remodeling in rats with acute myocardial infarction (AMI). METHODS: AMI was induced by ligating coronary artery in male Sprague Dawley rats. Two days after surgery, AMI rats received intravenous infusion of rhBNP (15 microg/kg or 5 microg/kg once daily, n = 15 each) or saline (placebo control, n = 15) through Jugular Vein. Sham-operated rats (n = 15) served as normal control. Four weeks later, hemodynamic measurements were performed, left ventricular weight (LVW), ratio of left ventricular weight to body weight (LVW/BW), left ventricular diameter (LVD) and infarct size were determined. Plasma angiotensin II and myocardial angiotensin II levels were also measured. RESULTS: Compared with sham-operated rats, LVW, LVW/BW, LVD and myocardial angiotensin II level were significantly increased, while the LV systolic pressure (LVSP), +/- dp/dt were significantly reduced in saline treated AMI rats (all P < 0.05). LVW/BW, MI size, LVD and myocardial angiotensin II in rhBNP treated AMI rats were significantly lower [LVW: (492.6 +/- 34.0) mg, (498.8 +/- 47.8) mg, (570.0 +/- 24.2) mg, P < 0.01; LVW/BW: 2.0 +/- 0.2, 2.0 +/- 0.2, 2.3 +/- 0.1, P < 0.01; LVD: (25.3 +/- 2.9)%, (31.4 +/- 3.0)%, (46.4 +/- 3.0)%, P < 0.01; myocardial angiotensin II: (881.3 +/- 62.7) pg/L, (1186.0 +/- 94.5) pg/L, (2436.7 +/- 280.3) pg/L, P < 0.05], while LVSP and +/- dp/dt in rhBNP treatment groups were significantly increased than saline treated AMI rats (P < 0.05 or P < 0.01). CONCLUSION: RhBNP is effective in attenuating left ventricular remodeling after AMI in rats.