Paclitaxel (Taxol), PTX) is a promising anti-cancer drug and has been successfully used to treat a wide variety of cancers. Unfortunately, serious clinical side effects are associated with it, which are caused by PTX itself and non-aqueous vehicle containing Cremophor EL. Development of new formulation of PTX with better efficacy and fewer side effects is extremely urgent. In the present study, a N-octyl-O-sulfate chitosan (NOSC) micelle was developed and used as the delivery system for PTX. The pharmacokinetics, biodistribution, efficacy and safety of PTX-loaded NOSC micelles (PTX-M) were evaluated. The results showed that NOSC micelles had high drug loading capacity (69.9%) and entrapment efficiency (97.26%). The plasma AUC of PTX-M was 3.6-fold lower than that of Taxol; but the V(d) and CL of PTX-M were increased by 5.7 and 3.5-fold, respectively. Biodistribution study indicated that most of the PTX were distributed in liver, kidney, spleen, and lung and the longest retention effect was observed in the lung. Drug safety assessment studies including acute toxicity, hemolysis test, intravenous stimulation and injection anaphylaxis revealed that the PTX-M was safe for intravenous injection. Furthermore, the comparable antitumor efficacy of PTX-M and Taxol was observed at the same dose of 10 mg/kg in in vivo antitumor mice models inoculated with sarcoma180, enrich solid carcinoma (EC), hepatoma solidity (Heps), Lewis lung cancer cells and A-549 human lung cancer cells. These results clearly showed that PTX-M had the similar antitumor efficacy as Taxol, but significantly reduced the toxicity and improved the bioavailability of PTX. 相似文献
Clinical outcome of spinal cavernous malformation (SCM) varies because of its unclear natural history, and reliable prognostic prediction model for SCM patients is limited. The aim of the present study was to investigate potential factors that predict one-year neurological status in postoperative patients with SCM.
Methods
This was a multicenter prospective observational study in consecutive patients with SCMs. SCMs treated microsurgically between January 2015 and January 2021 were included. Outcome was defined as the American Spinal Injury Association Impairment Scale (AIS) grade at one year after operation. Multivariable analyses were used to construct the best predictive model for patient outcomes.
Results
We identified 268 eligible SCM patients. Neurological outcome had worsened from preoperative baseline in 51 patients (19.0%) at one year. In the multivariable logistic regression, the best predictive model for unfavorable outcome included symptom duration ≥ 26 months (95% CI 2.80–16.96, P < 0.001), size ≤ 5 mm (95% CI 1.43–13.50, P = 0.010), complete intramedullary (95% CI 1.69–8.14, P = 0.001), subarachnoid hemorrhage (95% CI 2.92–12.57, P < 0.001), AIS B (95% CI 1.91–40.93, P = 0.005) and AIS C (95% CI 1.12–14.54, P = 0.033).
Conclusions
Admission size of the lesion, morphology, symptom duration, AIS grade and the presence of subarachnoid hemorrhage were strong outcome predictors regarding prognostication of neurological outcome in postoperative patients with SCMs. A decision to surgically remove a symptomatic SCM should be justified by systematic analysis of all factors potentially affecting outcome.
Objective To establish a porcine model of cardiopulmonary resuscitation to explore the effectiveness of resolvin Dl in improving post-resuscitation myocardial dysfunction and its potential mechanisms. Methods Twenty-eight male domestic pigs weighing 36 ± 3 kg were utilized. The pig model was established by 8 mins of untreated ventricular fibrillation and then 5 mins of cardiopulmonary resuscitation. The animals were randomly divided into 4 groups (n = 7 each): sham operation group (group S), cardiopulmonary resuscitation group (group CPR), low-dose resolvin Dl group (group LRD), and high-dose resolvin Dl group (group HRD). The animals in group S only got the general preparation without the procedure of cardiac arrest and resuscitation. At 5 rain after resuscitation, the doses of resolvin Dl 0. 3 gig/kg and 0. 6 kg/kg were respectively injected via the femoral vein of pigs in LRD and HRD groups, and meanwhile the equal volume of vehicle was given into the animals in the other two groups. At 3 h, 6 h and 24 h after resuscitation, the changes of stroke volume (SV) and global ejection fraction (GEF) were evaluated by a PiCCO monitor, and meanwhile the concentration of cardiac troponin I (cTNI) in serum was measured. At 24 h after resuscitation, the pigs were sacrificed, and myocardial tissue was obtained for the determination of tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), malondialdehyde (MDA), and superoxide dismutase (SOD) activity. Results Compared with group S, significantly decreased SV and GEF and markedly increased concentration of serum cTNI were observed in the other three groups with post-resuscitation myocardial dysfunction (all P <0. 05). Compared with group CPR, the values of SV and GEF were significantly increased while the concentration of serum cTNI was significantly decreased in LRD and HRD groups [SV (nil): 28±5, 31 ±5 vs. 23 ±4 at 3 hrs, 32±3, 36±6 vs. 27 ± 6at6hrs,35±5,4l±5vs.29±5at24hrs;GEF(%):l7±2,19i2vs.l4±lat3hrs,20±2,23 ±3 vs. 16±3 at6 hrs, 23±2, 26±3 vs. 20±2 at 24 hrs; cTNI (pg/nil):247±34, 230 ±26 vs. 324 ± 56 at3 hrs, 553 ±37, 501 ±34 vs. 611 ±44 at 6 hrs, 436 ±23, 371 ±29 vs. 553 ±47 at24 hrs, all P< 0. 05]. Compared with group LRD, myocardial function and serum markers were further significantly improved in group HRD (all P <0. 05). The inflammation and oxidative stress in myocardial tissue were observed in all the animals experiencing cardiac arrest and resuscitation, which were indicated by increased levels of TNF-a, IL-6 and MDA and decreased SOD activity. Compared with group CPR, the levels of TNF-a, IL-6 and MDA were significantly decreased while SOD activity was significantly increased in LRD and HRD groups [TNF-A (pg/mi): 442 ±87, 218 ±55 vs. 653 ± 112; IL-6 (pg/nil): 563 ± 68, 403±61 vs. 824±117; MDA (nmol/mg):3. 95±0. 96,2. 54±1. 2lvs. 6. 37±1. 26; SOD (U/mg): 2. 27±0. 93, 3. 36±0. 74 vs. 0. 89±0. 31, all P<0. 05). The morbidity of myocardial inflammation and oxidative stress were further significantly ameliorated in group HRD evidenced by the figure of biomarkers compared with group LRD (all P <0. 05). Conclusions Resolvin Dl can improve post-resuscitation myocardial dysfunction in a dose-dependent manner in swine, and the mechanism is related to the inhibition of inflammation and oxidative stress. 相似文献
Amphenicols are effective, broad-spectrum antibiotics that function by inhibiting the peptidyl transferase activity of bacteria, while the drugs can also inhibit mitochondrial protein synthesis in eukaryotes through the same mechanism, which leads to multi-organ toxicity. Some side effects of each drug have been studied, while differences in the severity of the hemotoxicities and immunotoxicities of amphenicols have not been reported. Thus, it is important to identify, evaluate, and compare the potential hemotoxicities and immunotoxicities to guide their proper use in humans and animals, which will guarantee food safety and animal welfare. Ovalbumin-immunized Kunming mice were gavaged daily with amphenicols for seven days. Blood samples were collected for hematology analysis, and measuring anti-ovalbumin antibody levels and serum intereukin-2 concentrations. The bone marrow, spleen and thymus were collected for histopathology and apoptosis analyzes. Bone marrow nucleated cells (BMNCs) and splenocytes were harvested to determine their cell cycle stages and to analyze lymphocyte proliferation. The results demonstrated that amphenicols, especially florfenicol (FLO), induced cell cycle arrest and apoptosis of hematopoietic cells, and it changed the bone marrow hematopoietic microenvironment by decreasing the number of peripheral blood cells. Moreover, amphenicols, especially FLO, induced hypoplasia and atrophy of the spleen and thymus, induced cell cycle arrest, as well as splenocyte apoptosis, and decreased the proliferation and viability of lymphocytes and the humoral and cellular immunity of the treated mice. These results suggest that amphenicols induce hemotoxicity and immunotoxicity to some extent, and that FLO induces more severe toxicity than equal doses of chloramphenicol (CAP) and thiamphenicol (TAP). 相似文献