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排序方式: 共有81条查询结果,搜索用时 31 毫秒
1.
Robert H. Smallwood George W. Mihaly Richard A. Smallwood Denis J. Morgan 《Journal of pharmacokinetics and pharmacodynamics》1988,16(5):529-542
For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu
b
)on steady state total (C
b
)and unbound (Cu
b
)blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL
int
).For a substance of very low CL
int
,if fu
b
changes, C
t
will change and Cu
b
will remain constant, whereas if CL
int
isvery high, Cu
b
will change and C
b
will remain constant.The present study defines the effects of a change in fu
b
on C
b
and Cu
b
over the whole CL
int
range. Computer simulations were undertaken which predicted that, for a given change in fu
b
,absolute and relative changes in C
b
would decreasenonlinearly with increasing CL
int, twhile the relative change in Cu
b would increasewith CL
int
.The absolute change in Cub
would be independent of CL
int
.Significant changes in Cb and Cu
b would be observed at intermediate values of CL
int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu
b of sodium taurocholate a substance with intermediate CL
int
(such that at fu
b
=0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24-
14
C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu
b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate C
b of 22.7% and a relative decrease in Cu
b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.This study was supported by the National Health and Medical Research Council of Australia. 相似文献
2.
3.
Sindiyan Alshaikh Mubarak Abeer Al Otaibi Ali Al Qarni Ahmed Bakillah Jahangir Iqbal 《Nutrients》2022,14(17)
Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38–45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress. 相似文献
4.
Yuejiao Yang Jie Chen Walter Bonani Bin Chen Sabrina Eccheli Devid Maniglio 《Journal of biomaterials science. Polymer edition》2018,29(10):1219-1231
Silk fibroin has acquired increasing interest in the last years for application in medicine and namely in tissue engineering. Several methods have been developed to process fibroin and for the fabrication of nets, sponges, films and gels. This paper deals with the fabrication and characterization of fibroin hydrogels obtained by using sodium oleate as gelation agent. Gels have been prepared by mixing Silk fibroin (SF) and Sodium oleate (SO) water solutions in different concentrations, and a quite wide frame of compositions have been explored. Rheological tests have been performed to determine the gelation times, scanning electron microscopies have been made to evaluate morphologies, FTIR analysis has been done to determine the conformation of the starting materials and of the resulting gels, water content has been measured and cytotoxicity tests have been performed to validate the potential biomedical use of the hydrogels. Depending on the SF and SO different gelation times have been obtained thanks to the formation of intermolecular bonds between the fibroin chains. The obtained fastest gelation of about 80 s could make this specific formulation compatible with in situ gelation. By changing composition, gels with different morphologies, rheological properties and water contents have been prepared. 相似文献
5.
Gotoh Y Iwakiri R Sakata Y Koyama T Noda T Matsunaga C Ogata SI Ishibashi S Sakata H Tsunada S Fujimoto K 《Journal of gastroenterology and hepatology》1999,14(3):241-244
BACKGROUND: To evaluate the efficacy of endoscopic variceal ligation (EVL) in prophylactic therapy for oesophageal varices, we performed a randomized prospective trial to compare the recurrence of oesophageal varices treated by EVL with those treated by endoscopic injection sclerotherapy. METHODS: Fifty patients with liver cirrhosis were divided into two groups at random, after informed consents were obtained, to receive prophylactic therapy for bleeding of oesophageal varices. Group 1 patients underwent sessions of sclerotherapy with 5% ethanolamine oleate used as the sclerosant. Group 2 patients underwent EVL followed by one or two sessions of sclerotherapy. RESULTS: During the 18 month follow-up period, both the recurrence rate in group 2 (56%) and the incidence of bleeding (20%) were significantly higher compared with group 1 (recurrence rate 16%, bleeding 0%). CONCLUSIONS: This result indicates that EVL is not effective for prophylactic therapy for oesophageal varices in liver cirrhosis. 相似文献
6.
目的 比较化学促渗剂和负极性驻极体对5-氟尿嘧啶(5-FU)体外经增生性瘢痕皮肤的促渗作用,为驻极体5-FU缓控释贴剂的制备奠定基础。方法 通过Franz扩散池和高效液相色谱仪,研究1%氮酮、10%油酸乙酯、-1 000 V驻极体、-1 500 V驻极体和-2 000 V驻极体作用后5-FU的体外经大鼠瘢痕皮肤或背部皮肤的透皮规律。结果 (1)1%氮酮和10%油酸乙酯均可促进5-FU经大鼠瘢痕皮肤的渗透,且10%油酸乙酯的促渗效果优于1%氮酮。(2)化学促渗剂作用下的5-FU经大鼠瘢痕皮肤和背部皮肤的体外渗透规律相似,但是5-FU经瘢痕皮肤的累积透皮量少于经背部皮肤的累积透皮量。(3)负极性驻极体对5-FU均具有良好的促渗作用,促渗效果的优劣顺序依次为:-2 000 V驻极体、-1 500 V驻极体、-1 000 V驻极体。同样,负极性驻极体作用下5-FU经大鼠瘢痕皮肤的累积透过量少于经背部皮肤的累积透皮量。结论 化学促渗剂和负极性驻极体均能促进5-FU的经皮渗透。其中,10%油酸乙酯和-2 000 V驻极体对5-FU的促渗效果最佳,可用于驻极体5-FU缓控释贴剂的制备。 相似文献
7.
Robert A. Egnatchik Alexandra K. Leamy Yasushi Noguchi Masakazu Shiota Jamey D. Young 《Metabolism: clinical and experimental》2014
Objective
Hepatic lipotoxicity is characterized by reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and excessive apoptosis, but the precise sequence of biochemical events leading to oxidative damage and cell death remains unclear. The goal of this study was to delineate the role of mitochondrial metabolism in mediating hepatocyte lipotoxicity.Materials/Methods
We treated H4IIEC3 rat hepatoma cells with free fatty acids in combination with antioxidants and mitochondrial inhibitors designed to block key events in the progression toward apoptosis. We then applied 13C metabolic flux analysis (MFA) to quantify mitochondrial pathway alterations associated with these treatments.Results
Treatment with palmitate alone led to a doubling in oxygen uptake rate and in most mitochondrial fluxes. Supplementing culture media with the antioxidant N-acetyl-cysteine (NAC) reduced ROS accumulation and caspase activation and partially restored cell viability. However, 13C MFA revealed that treatment with NAC did not normalize palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. To directly limit mitochondrial metabolism, the complex I inhibitor phenformin was added to cells treated with palmitate. Phenformin addition eliminated abnormal ROS accumulation, prevented the appearance of apoptotic markers, and normalized mitochondrial carbon flow. Further studies revealed that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with phenformin but not NAC.Conclusion
Our results indicate that ROS accumulation in palmitate-treated H4IIEC3 cells occurs downstream of altered mitochondrial oxidative metabolism, which is independent of beta-oxidation and precedes apoptosis initiation. 相似文献8.
Takeru Wakatsuki Katsutoshi Obara Atsushi Irisawa Hiroaki Sakamoto Toshimitu Kuwana Fujio Takiguchi Ayako Saito Hideo Shishido Takuto Hikichi Hitoshi Oyama Goro Shibukawa Tadayuki Takagi Go Yamamoto Hidemichi Imamura Yuta Takahashi Ai Sato Masaki Sato Reiji Kasukawa Hiromasa Ohira 《Digestive endoscopy》2009,21(4):232-238
Background: The prognostic factors, including gastric variceal bleeding itself, in patients with gastric varices (GV) after endoscopic treatment remain unclear. The aim of this study was to analyze prognostic factors in patients with GV after endoscopic treatment as well as to evaluate safety and efficacy of our endoscopic treatment. Patients and Methods: This study enrolled 115 patients who underwent endoscopic treatment for GV between October 1988 and December 2003 using cyanoacrylate and 5% ethanolamine oleate. Successful hemostasis, recurrence rates, rebleeding rates, survival rates, complications and prognostic factors after the treatment were retrospectively reviewed. Results: Treatment sessions for GV were performed 3.4 ± 2.5 times. All cases, including 14 emergency cases, were treated successfully. The cumulative recurrence rates at 1, 3 and 5 years after the treatment were 7.0%, 15.6% and 20.0%, respectively, and the cumulative rebleeding rates at 1, 3 and 5 years were 3.5%, 8.7% and 14.8%, respectively. The overall survival rates were 78.3%, 63.7% and 51.5% at 1, 3 and 5 years, respectively. Grade B or C in Child–Pugh classification, emergency or elective cases, and association with hepatocellular carcinoma were identified as significant negative prognostic factors after endoscopic treatment by multivariate analysis. Although several complications were observed, there was no mortality. Conclusions: Grade B or C in Child–Pugh classification, emergency or elective situation, and association with hepatocellular carcinoma are negative prognostic factors after endoscopic treatment. 相似文献
9.
Inhibitive effects of glucose and free fatty acids on proliferation of human vascular endothelial cells in vitro 总被引:16,自引:0,他引:16
Objectives To investigate the effects of glucose and free fatty acids (FFAs) on the proliferation and cell cycle of human vascular endothelial cells in vitro , and to examine whether the combined presence of elevated FFAs and glucose may cross-amplify their individual injurious effects.Methods Cultured human vascular endothelial cells (ECV304) were incubated with various concentrations of glucose and/or FFAs (palmitate and/or oleate) for 24-96 h. Morphologic alterations were observed using a phase contrast microscope and an electron microscope. Inhibition of proliferation was measured by a colorimetric 3-[4, 5-dimethyl thiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell viability was determined using trypan blue exclusion. Distribution of cells along phases of the cell cycle was analyzed by flow cytometry. Results Glucose 15 or 30 mmol/L, palmitate (PA) 0.25 or 0.5 mmol/L, and oleate (OA) 0.5 mmol/L inhibited proliferation and accelerated death of endothelial cells in a dose-and-time-dependent manner. After treatment with elevated glucose and/or FFAs, the G(0)/G(1) phase cells increased, whereas S phase cells decreased, suggesting that high glucose and/or FFAs mainly arrested endothelial cells at G(0)/G(1) phase. The inhibitive rates of proliferation and population of dead cells in endothelial cells incubated with glucose plus FFAs (glucose 30 mmol/L+PA 0.25 mmol/L, glucose 30 mmol/L+OA 0.5 mmol/L, glucose 30 mmol/L+PA 0.25 mmol/L+OA 0.5 mmol/L) increased more markedly than those treated with high glucose or FFAs (PA and/or OA) alone. Conclusion Both high ambient glucose and FFAs can inhibit proliferation and accelerate death of endothelial cells in vitro. These changes were cross-amplified in the combined presence of high levels of glucose and FFAs. 相似文献
10.
Sclerotherapy for Simple Cysts with Use of Ethanolamine Oleate: Preliminary Experience 总被引:3,自引:0,他引:3
Yamamoto K Sakaguchi H Anai H Tanaka T Morimoto K Kichikawa K Uchida H 《Cardiovascular and interventional radiology》2005,28(6):751-755
We evaluated the efficacy of ethanolamine oleate (EO) as a sclerosing agent for a symptomatic hepatic or renal cyst. Seven
patients with symptomatic hepatic (n = 3) or renal cysts (n = 4) were treated by sclerotherapy with EO. The cyst size in the greater diameter ranged from 6 to 13 cm. The cyst was punctured
under ultrasound guidance, and after all of the cyst’s content was aspirated, an iodized contrast agent was injected to check
the absence of communication between the cyst and biliary tree, urinary tract, or vessels. Then, the solution of ethanolamine
oleate–iopamidol mixture (EOI) of 10% of the volume of the cyst’s content was injected via catheter. After 30 min, the injected
EOI was aspirated completely before catheter removal. A follow-up computed tomography scan was performed at 1 and 3 months
after treatment. The volume of the cyst and its reduction rate was calculated. In addition, symptoms and complications were
assessed. The volume of the cyst ranged from 64 to 636 ml (mean: 328 ml) before treatment. Three months after treatment, it
ranged from 2 to 50 ml (mean: 15ml) and the reduction rate of the cyst’s volume was more than 90% on average. Symptoms caused
by the cyst disappeared in all cases and no major complication was encountered. Although two patients had a low-grade fever
after sclerotherapy, it was easily controlled. It is suggested that the sclerotherapy with EO might be a safe, effective,
well-tolerated treatment for symptomatic hepatic or renal cysts. 相似文献