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21.
In this study calendering is used as a downstream technique to shape monolithic co-extruded fixed-dose combination products in a continuous way. Co-extrudates with a metoprolol tartrate-loaded sustained-release core and a hydrochlorothiazide-loaded immediate-release coat were produced and immediately shaped into a monolithic drug delivery system via calendering, using chilled rolls with tablet-shaped cavities. In vitro metoprolol tartrate release from the ethylcellulose core of the calendered tablets was prolonged in comparison with the sustained release of a multiparticulate dosage form, prepared manually by cutting co-extrudates into mini-matrices. Analysis of the dosage forms using X-ray micro-computed tomography only detected small differences between the pore structure of the core of the calendered tablet and the mini-matrices. Diffusion path length was shown to be the main mechanism behind the release kinetics. Terahertz pulsed imaging visualized that adhesion between the core and coat of the calendered tablet was not complete and a gradient in coat thickness (varying from 200 to 600 μm) was observed. Modulated differential scanning calorimetry and X-ray diffraction indicated that the solid-state properties of both drugs were not affected by the calendering procedure. 相似文献
22.
目的 探讨上调和下调Cox-2基因表达对食管癌EC9706细胞裸鼠移植瘤放射敏感性的影响。方法 构建针对Cox-2基因的siRNA载体及Cox-2基因真核表达载体,通过脂质体转染技术将其转入食管癌EC9706细胞,G418筛选得到稳定转染细胞系。荧光定量RT-PCR和Western blot分别检测细胞中Cox-2 mRNA和Cox-2蛋白表达水平;裸鼠移植瘤实验检测上调和下调Cox-2表达联合X射线照射对食管癌的生长抑制作用。结果 Cox-2下调组食管癌EC9706细胞内Cox-2基因表达明显降低,Cox-2上调组明显升高。Cox-2下调组裸鼠移植瘤平均体积明显小于对照组(F=34.26,P<0.05);Cox-2上调组的瘤体平均体积大于对照组(F=26.38,P<0.05)。20 Gy γ射线照射后Cox-2下调组瘤体平均体积较照射前明显减小(F=16.35,P<0.05);而上调组裸鼠皮下种植瘤平均体积较照射前无明显变化。结论 下调Cox-2表达能抑制人食管癌EC9706细胞裸鼠移植瘤的生长,增强瘤体的放射敏感性,上调Cox-2表达则使肿瘤辐射抗拒。 相似文献
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BackgroundEsophageal cancer (EC) with a high incidence of malnutrition is a highly malignant digestive tract tumor. We investigated the effect of enteral nutrition (EN) support combined with enhanced recovery after surgery (ERAS) on the nutritional status, immune function, and prognosis of patients with EC after Ivor-Lewis operation.MethodsOne hundred patients were randomly divided into the observation group (n=42) and the control group (n=58). The patients in observation group were treated with EN combined with ERAS intervention after Ivor-Lewis operation, and the patients in control group were treated with conventional postoperative EN intervention. The situation of operation, nutritional status, immune function recovery and prognosis between the two groups were compared.ResultsThere was no statistically significant difference in operation time or intraoperative blood loss between the two groups (P>0.05). The chest tube removal time and oral feeding time of the observation group after operation were shorter than those of the control group (P<0.05). After intervention, serum albumin (ALB), transferrin (TF), pre-albumin (PA) and hemoglobin (Hb) levels in both groups were significantly decreased. These indexes were significantly higher in the observation group than in the control group (P<0.05). There were no significant changes in the levels of immunoglobulin (Ig) A, IgG, and IgM, or the numbers of CD3+, CD4+ and CD4+/CD8+ T cells in the observation group before and after intervention (P>0.05); however those indexes were significantly decreased in the control group after the intervention (P<0.05). Interestingly, the levels of IgA, IgM, IgG, CD3+ T cells, CD4+ T cells and CD4+/CD8+ T cells in the observation group were significantly higher than those in the control group after intervention (P<0.05). The incidence of pulmonary infection in the observation group was significantly lower than that in the control group. The postoperative exhaust time, postoperative defecation time and postoperative hospital stay were shorter in the observation group than in the control group (P<0.05). There was no significant difference in hospitalization cost between the two groups (P>0.05).ConclusionsEN combined with ERAS was more beneficial to the improvement of nutritional status and immune function recovery of patients with EC after Ivor-Lewis operation. It also shortened the length of hospital stay. 相似文献
26.
Cristiano Spadaccio Federico De Marco Fabio Di Domenico Raffaella Coccia Mario Lusini Raffaele Barbato Elvio Covino Massimo Chello 《Thrombosis research》2014
Background
Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage.Methods
Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20 μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3 weeks Simvastatin regimen were similarly processed.Results
Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage.Conclusions
Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes. 相似文献27.
Heiko Rühl Lars Schröder Jens Müller Rolf Fimmers Shorena Sukhitashvili Julia Welz Walther C. Kuhn Johannes Oldenburg Christian Rudlowski Bernd Pötzsch 《Thrombosis research》2014
Introduction
The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.Materials and Methods
Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.Results
APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.Conclusions
This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors. 相似文献28.
《Renal failure》2013,35(3-4):377-384
Urinary excretion of renal brush border enzymes may serve as an early marker of renal injury. However, the distinction between physiological and pathological levels remains controversial, since enzymuria is affected by physiological parameters. To clarify the influence of diuresis, we investigated the urinary excretion of alanine-aminopeptidase (AAP; EC 3.4.11.2) as function of diuretic state. 17 healthy volunteers of both sexes were subjected to protocols with sudden or prolonged water load preceded and followed by a thirst period. Urinary excretion of AAP was measured using an enzyme kinetic assay. As expected AAP excretion increased with urine flow, the increments diminished yielding an overall excretion pattern that resembled saturation kinetics. This function is described by a mathematical model. This model assumes, that AAP is released in proximal tubules at a constant rate and reabsorbed or inactivated in the distal tubule and collecting duct. Non-linear fits of the model equation to our data allowed two parameters, χ and μ, to be defined. χ describes the rate of AAP release independent of urinary flow, and μ the ratio of distal tubular reabsorption or inactivation. If a substrate is not reabsorbed at all, μ approximates zero. Since μ fitted for AAP differed significantly from zero, this indicates reabsorption or inactivation of AAP in the distal nephron. Therefore, our study supports the theory of flow-dependent reabsorption or inactivation of AAP in the distal nephron. 相似文献
29.
Wei Wu Qiaobing Huang Jingxia Miao Mingjia Xiao Hongxia Liu Kesen Zhao Ming Zhao 《Burns : journal of the International Society for Burn Injuries》2013
We previously reported Rho kinase is involved in vessel hyper-permeability caused by burns. Here we further explore the Rho kinase downstream signaling, it is found that its specific inhibitor Y27632 significantly diminishes the activation of JNK and p38 MAPKs but not ERK that induced by serum from burned rats (burn-serum). JNK activation was found involved in the expression of HUVEC adhesion molecules following thermal injury, although not in the process of stress fiber formation. Inhibition of various MAPKs by specific inhibitors showed that SB203580 (inhibitor of p38), but neither SP600125 (inhibitor of JNK) nor PD98059 (inhibitor of ERK), abolish activation of the p38 downstream kinase MK2. Demonstration of stress fibers by fluorescent-labeled phalloidin showed that inhibition of MK2, either by its specific inhibitor or by dominant negative adeno-viral-carried constructs, significantly reduced burn-serum-induced HUVEC stress-fiber formation, while inhibition of another downstream p38 MAPK kinase, PRAK, had no such effects. Transfection of dominant negative adeno-viral MK2 (Ad-MK2(A)) significantly inhibited thermal injury-induced blood vessel hyper-permeability in rats and, moreover, prolonged the survival of burned rats beyond 72 h following thermal injury. One of the mechanisms behind these phenomena is that Ad-MK2(A) causes a significant depression of burn-serum-induced HSP27-phosphorylation, while the adeno-viral transported dominant negative PRAK (Ad-PRAK(A)) does not block. Although the effect of blockade of MK2 through its adeno-viral approach requires further study and investigation of alternatives to know for sure, we may have found a new pathway behind thermal-injury-induced blood vessel hyper-permeability, namely: Rho kinase > p38 > MK2 > HSP27. 相似文献
30.
Morgan E. Gibbs Laura A. Wilt Kaitlyn V. Ledwitch Arthur G. Roberts 《Journal of pharmaceutical sciences》2018,107(7):1937-1947
P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide. 相似文献