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Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days , with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of Shenmai injection on vascular endothelial active facters nitric oxide (NO) and endothelin-1 (ET-1), and pulmonary gas exchange induced by tourniquet deflation in patients undergoing lower extremity surgery.</p><p><b>METHOD</b>Twenty-six patients scheduled for unilateral lower extremity surgery were randomly divided into 2 groups: control group (group C, n = 14) and Shenmai injection group (group SM, n = 12). All the patients agreed to a combined spinal-epidural anesthesia at the L2-L3 interspace and a radial artery catheter was placed for sampling. Patients in group SM were injected Shenmai injection 0.6 mL x kg(-1) and physiological saline 100 mL, while patients in group C were injected equal volume of normal saline instead 15 min before tourniquet inflation. Blood samples which were used for blood gas analysis and measurement of nitric oxide (NO) and endothelin-1 (ET-1) were taken before tourniquet inflation (T0, baseline) and 30 min (T1), 2 h (T2), 6 h (T3), 24 h (T4) after tourniquet deflation.</p><p><b>RESULT</b>Compared with the baseline values at T0, in group C at T3 P(a) O2 and the levels of NO were significantly decreased, while P(A-a) DO2 and the levels of ET-1 at T3 were significantly increased (P < 0.05 or P < 0.01), in group SM, the levels of NO at T3 were significantly decreased (P < 0.05). Compared with group C, the changes of P(a)O2, P(A-a) DO2, NO and ET-1 were significantly mitigated in group SM.</p><p><b>CONCLUSION</b>The concentrations of NO and ET-1 is connected with the pulmonary gas exchange impairment induced by tourniquet application. Shenmai injection can improve the pulmonary gas exchange based on rising the level of NO, reducing the level of ET-1.</p>
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Drug Combinations , Drugs, Chinese Herbal , Pharmacology , Endothelin-1 , Blood , Metabolism , Endothelium, Vascular , Metabolism , Injections, Intravenous , Nitric Oxide , Blood , Metabolism , Pulmonary Gas Exchange , TourniquetsABSTRACT
AIM: To investigate the effects of non-invasive ischemic preconditioning on nitric oxide (NO)/endothelin-1 (ET-1) imbalance and gas exchange impairment following limb ischemia reperfusion in patients undergoing unilateral lower extremity surgery with tourniquet. METHODS: Twenty-seven patients aged 25-65 years, whose tourniquets duration varied from 1 h to 1.5 h and matched American Society of Anesthesiologists Physical Status Ⅰ-Ⅱ, were randomized into two groups: a control group (n=14) and a ischemic preconditioning group (IPC group, n=13) in which patients received three cycles of 5 min of ischemia/5 min of reperfusion before tourniquet inflation. Radial arterial blood gas, plasma malondialdehyde (MDA) and NO, serum ET-1 and interleukin-6 (IL-6) were measured just before tourniquet inflation(T_0), 1 h after inflation(T_1), and 0.5 h(T_2), 2 h(T_3), 6 h(T_4), 24 h(T_5) after tourniquet deflation. Meanwhile NO/ET-1 ratio, alveolar-arterial oxygen gradient (P_(A-a)DO_2) and intrapulmonary shunt (Qs/Qt) were calculated. RESULTS: In control group, arterial partial pressure of oxygen (PaO_2) were decreased, while P_(A-a)DO_2 and Qs/Qt were increased significantly at T_4 compared to the baselines at T_0 (P<0.01). Plasma NO levels and NO/ET-1 ratios decreased gradually after tourniquets deflation and statistical significances were observed at T_3 (P<0.01) with a valley at T_4 (P<0.01) and recovered to baselines at T_5. Serum ET-1, IL-6 and plasma MDA began to increase remarkably after T_3 (P<0.05 or P<0.01), peaked at T_4 and dropped slightly at T_5. The changes above-mentioned could be well attenuated by the application of IPC (P<0.05 or P<0.01) except PaO_2 (P>0.05). CONCLUSION: Clinical application of unilateral tourniquet within safe time limit (1.5 h) may lead to limb ischemia reperfusion and further pulmonary gas exchange impairment, which could be partially attenuated by the application of IPC via alleviating NO/ET-1 imbalance.
ABSTRACT
0.05).At the T1,T3,T4,T7 time point,changes of the MAP and HR were more stable in TCI group than those in control group.The awakening time and extubation time in TCI group was obviously shorter in than that in control group.The OAAS scores after extubation were higher and the VRS scores 30 min after extubation were lower in TCI group than those in control group(P