[New progress in the first-line treatment of advanced hepatocellular carcinoma].

Hepatocellular carcinoma is a kind of cancer with a strong invasion, a high incidence rate and mortality, and a poor prognosis. At the time of diagnosis, most patients are already in the advanced stages of a tumor and have lost the chance for radical surgical treatment. Advanced hepatocellular carcinoma treatment has a gradual transition from systemic chemotherapy to targeted therapy, immunotherapy, and combination therapy, especially immune checkpoint inhibitor-based immunotherapy combination therapy, such as combination with bevacizumab monoclonal antibodies and other drugs, or combination with TACE, HAIC, radiotherapy, ablation, and other treatment methods. Combination therapy has significant synergistic effects and thus has already become a future treatment trend for hepatocellular carcinoma. An immunotherapy-based combination therapy plan will run through the whole process of systemic therapy, which is expected to bring better survival benefits to patients with hepatocellular carcinoma. This article reviews the latest research progress in aspects of the first-line treatment of advanced hepatocellular carcinoma.

Effects of captopril and enalaprilat on intracellular Ca2+, Na+ contents and pH in hypoxic and reoxygenated cardiomyocytes.

AIM: To study the mechanisms of captopril (Cap) and enalaprilat (Ena) protective effects on hypoxic and reoxygenated cardiac myocytes. METHODS: Using fluorescent probes Fura 2-AM, BCECF/AM, SBFI/AM combined with computer image processing techniques to measure intracellular ion concentrations. RESULTS: [Ca2+]i (165 +/- 8 nmol.L-1) and [Na+]i (9.2 +/- 0.8 mmol.L-1) were higher but [pH]i (6.7 +/- 0.3) was lower in hypoxic and reoxygenated myocytes (196 +/- 14 nmol.L-1, 9.3 +/- 1.3 mmol.L-1, 6.61 +/- 0.19, respectively) than in normal ones. Cap and Ena reduced [Ca2+]i (149 +/- 11 and 152 +/- 10 nmol.L-1 respectively) and intracellular acidosis (7.11 +/- 0.22 and 7.2 +/- 0.4, respectively) during hypoxia. Cap also decreased [Na+]i in hypoxic myocytes (8.1 +/- 0.9 mmol.L-1). During reoxygenation, Cap decreased [Ca2+]i and [Na+]i but Ena had no significant effect on them. Cap or Ena had no additive effect when combined with verapamil (Ver). CONCLUSION: Cap and Ena protected hypoxic and reoxygenated cardiomyocytes, but the mechanisms were not the same.

Effect of captopril on intracellular pH in vascular smooth muscle cells.

AIM: To observe the effect of captopril (Cap) on intracellular pH (pHi) in aortic smooth muscle cells (ASMC). METHODS: Cultured ASMC derived from rat and rabbit aortae were loaded with the fluorescent dye BCECF and pHi was determined using digital image processing method. RESULTS: The pHi of untreated SHR and WKY rats were 7.37 +/- 0.29 and 7.19 +/- 0.31, respectively. Oral Cap decreased pHi (7.11 +/- 0.26, P < 0.05) and exaggerated pHi response to angiotensin II (Ang-II, 0.1 mumol.L-1) in ASMC of SHR rats vs WKY rats (0.14 +/- 0.05 vs 0.21 +/- 0.05 pH units, P < 0.01). Cap in vitro had no effect on Ang-II induced intracellular alkalinization in ASMC of rabbits. CONCLUSION: Oral Cap inhibits Na+(-)H+ exchange activity in ASMC of SHR rats.

Effects of captopril and enalaprilat on intracellular Ca2+ content in isolated cardiomyocytes from rats.

AIM: To study the effects of ACEI captopril (Cap) and enalaprilat (Ena) on intracellular Ca2+ concentration ([Ca2+]i) in cardiac myocytes isolated from SHR and WKY rats. METHODS: Using fluorescent probe Fura 2-AM combined with computer image processing technique to measure [Ca2+]i. RESULTS: Resting [Ca2+]i was higher in SHR cardiac myocytes (174 +/- 5 nmol.L-1) than that in WKY rat myocytes (148 +/- 15 nmol.L-1, P < 0.01). Cap and Ena decreased the resting [Ca2+]i in SHR myocytes (161 +/- 11 and 166 +/- 7 nmol.L-1, respectively, P < 0.05) but not in WKY rat myocytes (P > 0.05). Both drugs inhibited [Ca2+]i increment induced by KCI, NE, or Ang II in SHR and WKY rat myocytes except on KCI-induced [Ca2+]i increment in WKY rat myocytes (P > 0.05). CONCLUSION: Cap and Ena had direct effects on pathological voltage-operated calcium channel in cardiac myocytes.

Effects of captopril and enalapril on intracellular Ca2+ in vascular smooth muscle cell.

AIM: To determine whether angiotensin-converting enzyme inhibitors can affect Ca2+ handling in cultured aortic smooth muscle cells (ASMC) directly. METHODS: Cultured ASMC derived from rat aorta were loaded with the intracellular Ca2+ ([Ca]2+i) fluorescent indicator Fura 2-AM and digital image processing technique was used. RESULTS: Resting [Ca2+]i was greater in ASMC from SHR vs WKY (P < 0.01). KCl-, norepinephrine (NE)-, and angiotensin II (Ang)-induced [Ca2+]i increases were enhanced in ASMC of SHR vs WKY (220 +/- 6, 212 +/- 8, and 215 +/- 14 vs 199 +/- 6, 202 +/- 7, and 195 +/- 7 nmol.L-1, respectively). Captopril (Cap) and enalapril (Ena) had no inhibitory effect on KCl-, NE-, and Ang-induced [Ca2+]i increases in ASMC of WKY. Cap and Ena inhibited KCl-, NE-, and Ang-increased [Ca2+]i in ASMC of SHR (210 +/- 7, 194 +/- 6, and 201 +/- 6 nmol.L-1, respectively). Ena and nifedipine similarly decreased KCl-, NE-, and Ang-increased [Ca2+]i. CONCLUSION: Cap blocked KCl-, NE-, and Ang-increased ([Ca2+]i) via a voltage-dependent Ca2+ channel of which function and specificity was altered in ASMC of SHR.

Retinal toxicity in albino rabbits induced by intravitreal injection of strophanthin-K.

Time course and extent of strophanthin-K induced disturbances of flash electroretinogram (F-ERG) has been observed in 12 albino rabbits treated by a single dose of 1, 3 and 9 ug/0.1 ml of intravitreal injection. A phenomenon of the dependence of a- and b-wave amplitude changes on dosage was demonstrated. A 9 ug/0.1 ml dose caused a flat a- and b-wave showing the F-ERG wave could be completely suppressed by larger dose of strophanthin-K. Two parameters of "attenuation kinetics" are proposed to identify the pharmacodynamics and toxic kinetics on retina as time profile is concerned: 1) B (the slope of attenuation curve); 2) Et1/2 (half attenuative time). B and Et1/2 are helpful in making a tentative identification of the target cells on retina and in demonstrating a synergism or antagonism between drugs if any. The a-wave of F-ERG, having a steeper slope, is more sensitive than b-wave in terms of strophanthin-K toxicity bringing forth a quantitative criterion in visual pharmacology. The attenuation of amplitude in a-wave may therefore be considered as an early response to this drug. The direct pupillary response test were also done pre- and post-strophanthin-K, and the results of this test support that of F-ERG.

[Electrophysiological effects of changrolin on single ventricular myocytes isolated from adult guinea pig].

Calcium tolerant single ventricular cardiomyocytes were dispersed from adult guinea pig hearts by retrograde perfusion with collagenase solution. More than 50% of the isolated cells retained rod shaped configuration and showed normal electrical activities with resting potentials (RP) at -82 +/- 2 mV and action potential amplitude (APA) at 116 +/- 6 mV. The effects of changrolin (CRL, 4-[3', 5'-bis [(N-pyrrolidinyl)-methyl]-4'-hydroxyanilino]-quinazoline) on the transmembrane action potentials of the single cells were measured with intracellular glass microelectrodes. At the concentration of 50 mumol/L, CRL caused profound reductions of APA, maximal rate of phase 0 depolarization (Vmax), and action potential duration (APD). The effective refractory period (ERP) was prolonged. The action of CRL on Vmax showed use- and frequency-dependences. Trains of stimuli in the studied range of frequencies led to an exponential decline in Vmax to a new plateau and the maximal reduction was at the highest frequency. At 1 Hz, the onset rate of this action was 0.036 +/- 0.004 AP-1. CRL did not cause a resting state block of Vmax. These findings suggest that CRL is a slow type, class I anti-arrhythmia drug.

[Effects of guan-fu base A on fast response action potentials of papillary muscles of guinea pigs].

Guan-fu base A is a new alkaloid first isolated from the tuber of Aconitum coreanum in China. The electrophysiological effects of guan-fu base A were examined on the isolated papillary muscles of guinea pigs by glass-microelectrode technique coupled with microcomputer real-time analysis. Guan-fu base A 50 micrograms/ml had less effect on RP, but markedly decreased Vmax and APA of the fast response action potentials. The action potential duration was shortened at all voltage levels and plateau height was lowered. ERP was prolonged relatively and activation voltage became more negative. The inhibition of guan-fu base A on Vmax showed frequency dependent effects. The above results suggested that guan-fu base A could block the fast Na+ channels and exhibited anti-arrhythmic action.

Effect of higenamine on action potential of ventricular myocardial cells.

Action potentials of isolated ventricular myocardial fibers of pigs and the electrophysiological actions of dl-demethylcoclaurine (DMC) or higenamine on the porcine myocardial cells were studied by glass microelectrodes. The action potentials of porcine ventricular myocardial fibers were similar to those of other mammalian hearts. Amplitude of the action potential was 115 +/- 9 mV, duration of action potential 242 +/- 30 ms, resting membrane potential -85 +/- 5 mV and the maximum rise of depolarization of action potential 151 +/- 27 V/s. After perfusion with normal Tyrode's solution containing DMC 5 micrograms/ml, the amplitude of action potential was increased and the duration of action potential was prolonged, the amplitude and duration of the plateau of action potential were increased and the slope of phase 2 of action potential was reduced (p less than 0.05). The resting potential, the slope of phase 3 and the maximum depolarization rate of phase 0 of action potential did not change. In Tyrode's solution containing Mn++ 3 mM, these electrophysiological actions of DMC disappeared. DMC may abolish the conduction block induced by K+-rich solution. In Tyrode's solution containing K+ 32 mM, the upstroke of action potential showed 2 phases under influence of DMC. The second phase disappeared when Mn++ was added. All findings indicate that DMC can be considered as an activator of the slow channel. The electrophysiological mechanism and clinical significance of DMC were discussed.