Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg...Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg/（m^2-min）] on days 1 and 8 plus carboplatin AUC （area under curve） 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Methods： Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. Results： The obtained mean parameters, such as T1/2 （elimination half time）, AUC, and CL （clearance）, were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR ann. Additional 50% and 33.3% patients contracted stable disease （SD） in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion ann experienced consistently more hematologic toxicity, Conclusion： Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.展开更多
Background Cilostazol is a type 3 phosphodiesterase inhibitor which has been previously demonstrated to prevent the occurrence of tachyarrhythmia and improve defibrillation efficacy. However, the mechanism for this be...Background Cilostazol is a type 3 phosphodiesterase inhibitor which has been previously demonstrated to prevent the occurrence of tachyarrhythmia and improve defibrillation efficacy. However, the mechanism for this beneficial effect is still unclear. Since cardiac mito-chondria have been shown to play a crucial role in fatal cardiac arrhythmias and that oxidative stress is one of the main contributors to arr-hythmia generation, we tested the effects of cilostazol on cardiac mitochondria under severe oxidative stress. Methods Mitochondria were isolated from rat hearts and treated with H2O2 to induce oxidative stress. Cilostazol, at various concentrations, was used to study its protective effects. Pharmacological interventions, including a mitochondrial permeability transition pore （mPTP） blocker, cyclosporine A （CsA）, and an inner membrane anion channel （IMAC） blocker, 4＇-chlorodiazepam （CDP）, were used to investigate the mechanistic role of cilostazol on cardiac mitochondria. Cardiac mitochondrial reactive oxygen species （ROS） production, mitochondrial membrane potential change and mi-tochondrial swelling were determined as indicators of cardiac mitochondrial function. Results Cilostazol preserved cardiac mitochondrial function when exposed to oxidative stress by preventing mitochondrial depolarization, mitochondrial swelling, and decreasing ROS produc-tion. Conclusions Our findings suggest that cardioprotective effects of cilostazol reported previously could be due to its prevention of car-diac mitochondrial dysfunction caused by severe oxidative stress.展开更多
It is a promising treatment strategy to use a nanoparticle-based drug delivery system for cancer patients, which can simultaneously deliver multiple drugs or genes in combination with therapy to induce synergistic eff...It is a promising treatment strategy to use a nanoparticle-based drug delivery system for cancer patients, which can simultaneously deliver multiple drugs or genes in combination with therapy to induce synergistic effects and suppress drug resistance to the tumor. In this study, cationic nanostructured lipid carriers（cNLC） for co-loading anionic small-interfering RNAs（siRNA） and chemotherapeutic docetaxel（DTX） were prepared from different cationic lipids based on particle distribution and loading efficiency. In order to increase the cNLC＇s positive targeting capacity, a novel peptide SP94 was bound to the surface of cNLC（SP94-cNLC）. The cNLC showed good efficiency in loading siRNA and DTX. The SP94-cNLC revealed a better cytotoxicity compared with cNLC and Taxotere？, indicating that SP94 could successfully enhance the internalization capacity of nanoparticles to the liver cancer cells. This new type of cNLC is a potential vehicle when using in co-delivery of chemotherapeutics and siRNAs. The curcumin（CUR）/DTX co-delivery NLC could load both CUR and DTX in high efficiency and showed a sensibilization to DTX chemotherapy. The sensibilization was more obvious when it was used in the aggressive and resistant cancer cells. This CUR/DTX co-delivery system had good potential in treating cancer cells when chemotherapy drug showed little effect alone.展开更多
Physical performance is determined both by biophysical and physiological limitations and behav- ioral characteristic, specifically motivation. We applied an experimental evolution approach com- bined with pharmacologi...Physical performance is determined both by biophysical and physiological limitations and behav- ioral characteristic, specifically motivation. We applied an experimental evolution approach com- bined with pharmacological manipulation to test the hypothesis that evolution of increased aerobic exercise performance can be triggered by evolution of motivation to undertake physical activity. We used a unique model system： bank voles from A lines, selected for high swim-induced aerobic metabolism （VO2swim）, which achieved a 61% higher mass-adjusted VO2swim than those from un- selected C lines. Because the voles could float on the water surface with only a minimum activity, the maximum rate of metabolism achieved in that test depended not only on their aerobic capacity, but also on motivation to undertake intensive activity. Therefore, we hypothesized that signaling of neurotransmitters putatively involved in regulating physical activity （dopamine and noradrenaline） had changed in response to selection. We measured VO2swim after intraperitoneal injections of sa- line or the norepinephrine and dopamine reuptake inhibitor bupropion （20 mg/kg or 30 mg/kg）. Additionally, we measured forced-exercise VO2 （VO2max）. In C lines, VO2swim （mass-adjusted mean ± standard error （SE）： 4.0 ± 0.1 mLO2/min） was lower than VO2max （5.0 ± 0.1 mLO2/min）, but in A lines VO2swim （6.0 ± 0.1 mLO2/min） was as high as VO2max （6.0 ± 0.1 mLO2/min）. Thus, the selection effectively changed both the physiological-physical performance limit and mechanisms responsible for the willingness to undertake vigorous locomotor activity. Surprisingly, the drug had no effect on the achieved level of VO2swim. Thus, the results did not allow firm conclusions concerning involvement of these neurotransmitters in evolution of increased aerobic exercise performance in the experimental evolution model system.展开更多
基金Project (No.2004A028) supported by the Medical Science Research Foundation of Zhejiang Province,China
文摘Objective： To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m^2 gemcitabine using standard 30-min infusion or fixed dose rate （FDR） infusion [10 mg/（m^2-min）] on days 1 and 8 plus carboplatin AUC （area under curve） 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. Methods： Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. Results： The obtained mean parameters, such as T1/2 （elimination half time）, AUC, and CL （clearance）, were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR ann. Additional 50% and 33.3% patients contracted stable disease （SD） in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion ann experienced consistently more hematologic toxicity, Conclusion： Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.
文摘Background Cilostazol is a type 3 phosphodiesterase inhibitor which has been previously demonstrated to prevent the occurrence of tachyarrhythmia and improve defibrillation efficacy. However, the mechanism for this beneficial effect is still unclear. Since cardiac mito-chondria have been shown to play a crucial role in fatal cardiac arrhythmias and that oxidative stress is one of the main contributors to arr-hythmia generation, we tested the effects of cilostazol on cardiac mitochondria under severe oxidative stress. Methods Mitochondria were isolated from rat hearts and treated with H2O2 to induce oxidative stress. Cilostazol, at various concentrations, was used to study its protective effects. Pharmacological interventions, including a mitochondrial permeability transition pore （mPTP） blocker, cyclosporine A （CsA）, and an inner membrane anion channel （IMAC） blocker, 4＇-chlorodiazepam （CDP）, were used to investigate the mechanistic role of cilostazol on cardiac mitochondria. Cardiac mitochondrial reactive oxygen species （ROS） production, mitochondrial membrane potential change and mi-tochondrial swelling were determined as indicators of cardiac mitochondrial function. Results Cilostazol preserved cardiac mitochondrial function when exposed to oxidative stress by preventing mitochondrial depolarization, mitochondrial swelling, and decreasing ROS produc-tion. Conclusions Our findings suggest that cardioprotective effects of cilostazol reported previously could be due to its prevention of car-diac mitochondrial dysfunction caused by severe oxidative stress.
基金National Natural Science Foundation of China(Gr ant No.81273454)Beijing Natural Science Foundation(Grant No.7132113)Doctoral Foundation of the Ministry of Education(Grant No.20100001110056 and 20130001110055)
文摘It is a promising treatment strategy to use a nanoparticle-based drug delivery system for cancer patients, which can simultaneously deliver multiple drugs or genes in combination with therapy to induce synergistic effects and suppress drug resistance to the tumor. In this study, cationic nanostructured lipid carriers（cNLC） for co-loading anionic small-interfering RNAs（siRNA） and chemotherapeutic docetaxel（DTX） were prepared from different cationic lipids based on particle distribution and loading efficiency. In order to increase the cNLC＇s positive targeting capacity, a novel peptide SP94 was bound to the surface of cNLC（SP94-cNLC）. The cNLC showed good efficiency in loading siRNA and DTX. The SP94-cNLC revealed a better cytotoxicity compared with cNLC and Taxotere？, indicating that SP94 could successfully enhance the internalization capacity of nanoparticles to the liver cancer cells. This new type of cNLC is a potential vehicle when using in co-delivery of chemotherapeutics and siRNAs. The curcumin（CUR）/DTX co-delivery NLC could load both CUR and DTX in high efficiency and showed a sensibilization to DTX chemotherapy. The sensibilization was more obvious when it was used in the aggressive and resistant cancer cells. This CUR/DTX co-delivery system had good potential in treating cancer cells when chemotherapy drug showed little effect alone.
文摘Physical performance is determined both by biophysical and physiological limitations and behav- ioral characteristic, specifically motivation. We applied an experimental evolution approach com- bined with pharmacological manipulation to test the hypothesis that evolution of increased aerobic exercise performance can be triggered by evolution of motivation to undertake physical activity. We used a unique model system： bank voles from A lines, selected for high swim-induced aerobic metabolism （VO2swim）, which achieved a 61% higher mass-adjusted VO2swim than those from un- selected C lines. Because the voles could float on the water surface with only a minimum activity, the maximum rate of metabolism achieved in that test depended not only on their aerobic capacity, but also on motivation to undertake intensive activity. Therefore, we hypothesized that signaling of neurotransmitters putatively involved in regulating physical activity （dopamine and noradrenaline） had changed in response to selection. We measured VO2swim after intraperitoneal injections of sa- line or the norepinephrine and dopamine reuptake inhibitor bupropion （20 mg/kg or 30 mg/kg）. Additionally, we measured forced-exercise VO2 （VO2max）. In C lines, VO2swim （mass-adjusted mean ± standard error （SE）： 4.0 ± 0.1 mLO2/min） was lower than VO2max （5.0 ± 0.1 mLO2/min）, but in A lines VO2swim （6.0 ± 0.1 mLO2/min） was as high as VO2max （6.0 ± 0.1 mLO2/min）. Thus, the selection effectively changed both the physiological-physical performance limit and mechanisms responsible for the willingness to undertake vigorous locomotor activity. Surprisingly, the drug had no effect on the achieved level of VO2swim. Thus, the results did not allow firm conclusions concerning involvement of these neurotransmitters in evolution of increased aerobic exercise performance in the experimental evolution model system.
