Co-delivery of doxorubicin-dihydroartemisinin prodrug/TEPP-46 nano-liposomes for improving antitumor and decreasing cardiotoxicity in B16-F10 tumor-bearing mice.

In order to reduce the cardiotoxicity of doxorubicin (DOX) and improve its antitumor effect, dihydroartemisinin (DHA) and DOX prodrug (DOX-S-DHA) synthesized via a single sulfur bond was used with TEPP-46 to prepare nano-liposomes (DOX-S-DHA@TEPP-46 Lips). In which, TEPP-46 was expected to exert p53 bidirectional regulation to promote the synergistic antitumor effect of DOX and DHA while reducing cardiotoxicity. DOX-S-DHA@TEPP-46 Lips exhibited uniform particle size, good stability, and excellent redox-responsive activity. DOX-S-DHA@TEPP-46 Lips could significantly inhibit the proliferation of tumor cells, but had less cytotoxicity on normal cells. The presence of TEPP-46 increased the content of p53 protein, which further induced tumor cell apoptosis. DOX-S-DHA@TEPP-46 Lips had satisfactory long circulation to enhance the antitumor efficacy and reversed the cardiotoxicity of DOX in B16-F10 tumor-bearing mice. In conclusion, DOX-S-DHA@TEPP-46 Lips provides a new insight on creating sophisticated redox-sensitive nano-liposomes for cancer therapy as well as the decreased cardiotoxicity of DOX.

Pharmacokinetics and Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. METHODS: This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. RESULTS: In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR > 0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0-t) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) were evaluated by the average bioequivalence (ABE) method (SWR <  0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was <  0. The GMRs of AUC0-t and AUC0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0-t and AUC0-∞ (SWR <  0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was <  0. The GMRs of AUC0-t and AUC0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient. CONCLUSIONS: The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. TRIAL REGISTRATION: Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023).

Effect of genetic polymorphisms on the pharmacokinetics of gefitinib in healthy Chinese volunteers.

Gefitinib is the first-generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolised by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted.Forty-five healthy volunteers were administered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2).CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC0-t, AUC0-∞ and Cmax in carrier of AC genotype than in AA gen-otype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib.The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.

A Comparative Study of Clinical and Aortic Morphological Characteristics between Bovine Aortic Arch and Normal Aortic Arch in Patients with Acute Type B Aortic Dissection.

INTRODUCTION: The purpose of this study was to analyze the difference in clinical and aortic morphological features between the bovine aortic arch and normal aortic arch in patients with acute type B aortic dissection (aTBAD). METHODS: A total of 133 patients diagnosed with aTBAD were retrospectively collected. Based on aortic arch morphology, they were divided into the bovine aortic arch group (n = 20) and the normal aortic arch group (n = 113). Aortic morphological features were assessed on computed tomographic angiography. Clinical and aortic morphological features were then compared between the bovine aortic arch and normal aortic arch groups. RESULTS: Patients in the bovine aortic arch group were significantly younger and with higher weight and BMI than the normal aortic arch group (p < 0.001, p = 0.045, and p = 0.016, respectively). The total aortic length in the bovine aortic arch group was significantly shorter than that in the normal aortic arch group (p = 0.039). The tortuosity of descending thoracic aorta, the tortuosity of descending aorta, and the angulation of aortic arch were significantly lower in the bovine aortic arch group (p = 0.004, p = 0.015, and p = 0.023, respectively). The width of descending aorta, the height of aorta arch, and the angle of ascending aorta were significantly smaller in the bovine aortic arch group (p = 0.045, p = 0.044, and p = 0.042, respectively). CONCLUSION: When the aTBAD occurred, patients with bovine aortic arch were prone to be younger and with higher BMI than those with normal aortic arch. The aortic curvature and the total aortic length were lower in patients with bovine aortic arch.

The role of epicardial and pericoronary adipose tissue radiomics in identifying patients with non-ST-segment elevation myocardial infarction from unstable angina.

Objectives: This study aimed to ascertain if the radiomics features of epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) based on coronary computed tomography angiography (CCTA) could identify non-ST-segment elevation myocardial infarction (NSTEMI) from unstable angina (UA). Materials and methods: This retrospective case-control study included 108 patients with NSTEMI and 108 controls with UA. All patients were separated into training cohort (n = 116), internal validation cohort 1 (n = 50), and internal validation cohort 2 (n = 50) based on the time order of admission. The internal validation cohort 1 used the same scanner and scan parameters as the training cohort, while the internal validation cohort 2 used different canners and scan parameters than the training cohort. The EAT and PCAT radiomics features selected by maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were adopted to build logistic regression models. Finally, we developed an EAT radiomics model, three vessel-based (right coronary artery [RCA], left anterior descending artery [LAD], and left circumflex artery [LCX]) PCAT radiomics models, and a combined model by combining the three PCAT radiomics models. Discrimination, calibration, and clinical application were employed to assess the performance of all models. Results: Eight radiomics features of EAT, sixteen of RCA-PCAT, fifteen of LAD-PCAT, and eighteen of LCX-PCAT were selected and used to construct radiomics models. The area under the curves (AUCs) of the EAT, RCA-PCAT, LAD-PCAT, LCX-PCAT and the combined models were 0.708 (95% CI: 0.614-0.802), 0.833 (95% CI:0.759-0.906), 0.720 (95% CI:0.628-0.813), 0.713 (95% CI:0.619-0.807), 0.889 (95% CI:0.832-0.946) in the training cohort, 0.693 (95% CI:0.546-0.840), 0.837 (95% CI: 0.729-0.945), 0.766 (95% CI: 0.625-0.907), 0.675 (95% CI: 0.521-0.829), 0.898 (95% CI: 0.802-0.993) in the internal validation cohort 1, and 0.691 (0.535-0.847), 0.822 (0.701-0.944), 0.760 (0.621-0.899), 0.674 (0.517-0.830), 0.866 (0.769-0.963) in the internal validation cohort 2, respectively. Conclusion: Compared with the RCA-PCAT radiomics model, the EAT radiomics model had a limited ability to discriminate between NSTEMI and UA. The combination of the three vessel-based PCAT radiomics may have the potential to distinguish between NSTEMI and UA.

Radiomics Signatures of Carotid Plaque on Computed Tomography Angiography : An Approach to Identify Symptomatic Plaques.

PURPOSE: To develop and validate a combined model incorporating conventional clinical and imaging characteristics and radiomics signatures based on head and neck computed tomography angiography (CTA) to assess plaque vulnerability. METHODS: We retrospectively analyzed 167 patients with carotid atherosclerosis who underwent head and neck CTA and brain magnetic resonance imaging (MRI) within 1 month. Clinical risk factors and conventional plaque characteristics were evaluated, and radiomic features were extracted from the carotid plaques. The conventional, radiomics and combined models were developed using fivefold cross-validation. Model performance was evaluated using receiver operating characteristic (ROC), calibration, and decision curve analyses. RESULTS: Patients were divided into symptomatic (n = 70) and asymptomatic (n = 97) groups based on MRI results. Homocysteine (odds ratio, OR 1.057; 95% confidence interval, CI 1.001-1.116), plaque ulceration (OR 6.106; 95% CI 1.933-19.287), and carotid rim sign (OR 3.285; 95% CI 1.203-8.969) were independently associated with symptomatic status and were used to construct the conventional model and s radiomic features were retained to establish the radiomics model. Radiomics scores incorporated with conventional characteristics were used to establish the combined model. The area under the ROC curve (AUC) of the combined model was 0.832, which outperformed the conventional (AUC = 0.767) and radiomics (AUC = 0.797) models. Calibration and decision curves analysis showed that the combined model was clinically useful. CONCLUSION: Radiomics signatures of carotid plaque on CTA can well predict plaque vulnerability, which may provide additional value to identify high-risk patients and improve outcomes.

Adeno-associated virus mediated gene transfer of Shepherdin inhibits gallbladder carcinoma growth in vitro and in vivo.

Gene therapy, a significantly crucial strategy for treatment of malignancies, has been gradually accepted in recent years. However, this therapeutic approach has being facing great challenges concerning problems which include complicated development of cancer with multiple gene control, effective target shortage, low efficiency of gene transferring and safety of the vector delivery system. Shepherdin, a novel peptidomimetic molecule designed from Lys-79 to Leu-87 of survivin, has been identified as a tumor suppressor with the function that can not only competitively interfere with the interaction between survivin and Hsp90 (heat shock protein-90) leading to the degradation of survivin to anti-tumor, but also competitively target the ATP-dependent binding pocket of Hsp90 resulting in the dysfunction of Hsp90 chaperone to cell apoptosis via a mitochondrial dependent or independent pathway. In the present study, we designed and constructed a recombinant Adeno-associated virus (rAAV) loading fusion gene NT4-TAT-6His-Shepherdin. The expression of Shepherdin in gallbladder carcinoma (GBC) cells was detected and its strong inhibitory effects against GBC growth were evaluated after AAV mediated gene transfer of Shepherdin into GBC cells and xenograft tumors. MTT assay and flow cytometric analysis demonstrated that rAAV containing Shepherdin gene could significantly inhibit the growth of GBC and this effect was closely associated with apoptosis. These results indicated that rAAV-NT4-TAT-6His-Shepherdin may be considered a novel therapeutic strategy in the gene therapy for gallbladder carcinoma.

[Analyzing anti-cancer action mechanisms of dihydroartemisinin using gene chip].

OBJECTIVE: To understand the action mechanisms of artesunate on inhibiting leukaemia cell line K562 on the molecular level. METHOD: The gene chip was used to detect the expression panel of genes of leukaemia cell line K562 treated by dihydroartemisinin. K562 cells were treated with 1 x 10(-5), 4 x 10(-5), 16 x 10(-5), 64 x 10(-5), 256 x 10(-5) mol x L(-1) dihydroartemisinin for 24 h, and then studied the modality changes by invert microscope. The morphological changes of the nucleons were observed by Hoechst33342/PI staining. The cell cycle were examined by flow cytometry analysis (FCM). Total RNA samples were obtained by TRIzol and were reverse transcribed to the cDNA. The cDNA samples were hybridized to our gene chips. Hybridization signal were collected and analyzed following scanning by Gene Pix 4100A. RESULT: The numbers of drift cells were increased and the density of cells was decreased under invert microscope after K562 cells were treated with dihydroartemisinin for 24 h. Morphological changes of cell apoptosis such as karyopyknosis and conglomeration were observed by Hoechst 33342/PI staining. Flow cytometric analysis showed that cells were arrested in G2 phase. There were 13 differentially expressed genes identified. Hybridization analysis showed up-regulation of chk1 and down-regulation of PCNA, cyclinB1, cyclinD1, cyclinE1, cdk4, cdk2, E2F1, DNA-PK, DNA-Topo I, mcl-1, jNK, VEGF in the dihydroartemisinin-treated K562 cells. CONCLUSION: Dihydroartemisinin can Inhibit the leukaemia cell line K562 and exert its anti-cancer effect by altering the expression of these genes involved in cell cycle; dihydroartemisinin may act via apoptosis pathway.