A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non-Small Cell Lung Cancer: a Multicenter Phase I/II Study.

PURPOSE: To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non-small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II. PATIENTS AND METHODS: This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II. RESULTS: The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43-129). Among 209 response-evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2-59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9-92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1-9.2) and 7.5 months (95% CI: 6.0-8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4-not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related. CONCLUSIONS: Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.

[Antiarrhythmic effect of ethyl acetate extract from Chrysanthemum Morifolium Ramat on rats].

OBJECTIVE: To investigate the effect of ethyl acetate extract from Chrysanthemum Morifolium Ramat (CME) on experimental arrhythmia induced by ischemia/reperfusion or aconitine in rats and to explore its underlying mechanisms. METHODS: Arrhythmia model in intact rat was induced by aconitine (30 microg/kg body weight, i.v.). In isolated Langendorff perfused rat hearts, regional ischemia and reperfusion was induced by ligation and release of left anterior descending artery. The ventricular fibrillation threshold (VFT), effective refractory period (ERP), and diastolic excitation threshold (DET) in the isolated heart were measured. The action potentials of papillary muscle in rat right ventricle were recorded by conventional glass microelectrode technique. RESULTS: Compared with control group CME significantly decreased the number and duration of ventricular tachycardia (VT); delayed the occurrence of ventricular premature beats (VPB) and VT induced by aconitine. Arrhythmia score of the CME group was lower than that in aconitine-treated group. CME markedly prolonged the ERP and increased the VFT in the isolated perfused rat hearts during ischemia and reperfusion. CME prolonged action potential duration at 50% and 90% repolarization of the right ventricular papillary muscles and decreased the maximal rate of rise of the action potential upstroke, but did not affect the resting potential, amplitude of action potential. CONCLUSION: CME can reduce myocardial vulnerability and exerts its antiarrhythmic effects induced by aconitine or ischemia/reperfusion, which may be related to its prolongation of action potential duration and effective refractory period that enhance the electrophysiological stability of myocardiaium.

Salvia miltiorrhiza attenuates the changes in contraction and intracellular calcium induced by anoxia and reoxygenation in rat cardiomyocytes.

The aim of the present study is to investigate the effect of Salvia miltiorrhiza (SM) on contraction and the intracellular calcium of isolated ventricular myocytes during normoxia or anoxia and reoxygenation using a video tracking system and spectrofluorometry. Cardiac ventricular myocytes were isolated enzymatically by collagenase and exposed to 5 min of anoxia followed by 10 min of reoxygenation. SM (1-9 g/L) depressed both contraction and the [Ca(2+)](i) transient in a dose-dependent manner. SM did not affect the diastolic calcium level and the sarcolemmal Ca(2+) channel of myocytes but decreased the caffeine-induced calcium release. During anoxia, the +/-dL/dtmax, amplitudes of contraction (dL) of cell contraction and [Ca(2+)](i) transients were decreased, while the diastolic calcium level was increased. None of the parameters returned to the pre-anoxia level during reoxygenaton. However, SM (3 g/L) did attenuate the changes in cell contraction and intracellular calcium induced by anoxia and reoxygenation. It is concluded that SM has different effects on normoxic and anoxic cardiomyocytes. The SM-induced reduction of changes in contraction and intracellular calcium induced by anoxia/reoxygenation indicates that SM may be beneficial for cardiac tissue in recovery of mechanical function and intracellular calcium homeostasis.

[Role of interleukin-2 in the functional myocardial impairment induced by anoxia and reoxygenation].

OBJECTIVE: To investigate the effect of interleukin-2 (IL-2) on myocardial impairment during ischemia/reperfusion or anoxia/reoxygenation. METHODS: Chemical anoxia was introduced in the isolated rat ventricular myocytes by Krebs-Henseleit (K-H) solution containing 10(-3) mol/L sodium dithionite. The video-tracking system and spectrofluorometric method were employed to verify the cell contraction and calcium homeostasis of the single myocyte. Radioimmunoassay was used to analyze the IL-2 levels in myocardium. RESULTS: The levels of IL-2 in myocardium subjected to ischemia/reperfusion were elevated [(14.34+/-5.99 compared with 22.25+/-3.68)ng/g, P<0.01]. During anoxia, cell contraction and the amplitude of electrically induced calcium transient were depressed and the parameters did not return to the pre-anoxia level during reoxygenation. IL-2 at 200 U/L administered during anoxia aggravated the effect of reoxygenation on cell contraction and calcium transient. After perfusion with IL-2, the malondialdehyde content of myocardial mitochondria was elevated. CONCLUSION: Coexistence of IL-2 during anoxia aggravates the effect of reoxygenation on the cell contraction and calcium homeostasis in the isolated rat ventricular myocytes, in which the mitochondrial lipid peroxidation induced by IL-2 is involved.