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991.
A Folate Receptor–Targeted Lipid Nanoparticle Formulation for a Lipophilic Paclitaxel Prodrug 总被引:3,自引:0,他引:3
No HeadingPurpose. The anticancer drug paclitaxel has poor aqueous solubility and is difficult to formulate in a lipid-based formulation due to its limited lipid solubility. Paclitaxel-7-carbonyl-cholesterol (Tax-Chol), a prodrug of paclitaxel with increased lipophilicity, was therefore synthesized and evaluated for incorporation into a lipid nanoparticle (LN) formulation, which also contained folate-polyethylene glycol-cholesterol (f-PEG-Chol) as a ligand that targets the tumor marker folate receptor (FR). This novel formulation was designed for prolonged systemic circulation and selective targeting of tumor cells with amplified FR expression.Methods. Tax-Chol was synthesized. FR-targeted LNs, composed of distearoyl phosphatidylcholine (DSPC)/triolein/Chol oleate/PEG-Chol/f-PEG-Chol (40:40:18:2.0:0.5, mole/mole), were then prepared by solvent dilution followed by diafiltration. FR-targeted LNs containing Tax-Chol were then evaluated for cytotoxicity in KB, a human oral carcinoma cell line, and M109, a murine lung carcinoma cell line, both of which are FR(+) and in FR(–) Chinese hamster ovary (CHO) cells. Furthermore, tumor growth inhibition and animal survival in response to treatment with FR-targeted LNs and control formulations were evaluated in BALB/c mice bearing subcutaneously engrafted M109 tumors.Results. The LNs had a mean diameter of 130 nm and Tax-Chol incoporation efficiency of greater than 90% and exhibited excellent colloidal stability. FR-targeted LNs showed greater uptake and cytotoxicity in FR(+) KB and M109 cells than nontargeted LNs. Furthermore, treatment of mice bearing M109 tumors with FR-targeted LNs resulted in significantly greater tumor growth inhibition and animal survival compared to treatment with nontargeted LNs or paclitaxel formulated in Cremophor EL.Conclusions. FR-targeted LNs containing Tax-Chol are a promising novel formulation for the treatment of FR(+) tumors and further preclinical studies are warranted. 相似文献
992.
Effect of oestrogen replacement therapy on serum lipid profile 总被引:3,自引:0,他引:3
Nanda S Gupta N Mehta HC Sangwan K 《The Australian & New Zealand journal of obstetrics & gynaecology》2003,43(3):213-216
BACKGROUND: Oestrogen deficiency in postmenopausal women alters the lipid metabolism unfavourably. AIM: To evaluate the effects of oral and transdermal oestrogen replacement therapy (ORT) on serum lipid profile. METHODS: Ninety hysterectomised and oophorectomised women were randomised into three equal groups (no hormones; oral conjugated equine oestrogen, 0.625 mg/day; transdermal oestradiol patches, 50 microg/day). Serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides were determined at the baseline and after 3 and 6 months of therapy. Student's t-test was used for statistical evaluation. RESULTS: Most of the hysterectomised women had abnormal serum lipid profile, especially HDL cholesterol levels (less than 40 mg/dL in 87%). A significant decline in the levels of serum cholesterol (total) as well as LDL and a significant increase in HDL cholesterol levels were observed following ORT by both modes, the response being comparatively rapid with oral route. After 3 and 6 months, the number of cases with HDL cholesterol levels above 40 mg/dL increased from initial 13 to 63% and 87% (oral) and 30 and 60% (transdermal), respectively. Serum triglyceride levels declined significantly with transdermal therapy but increased with oral ORT. CONCLUSIONS: Oestrogen replacement therapy either via oral or transdermal route has a beneficial effect on serum lipid profile of menopausal women. Whereas the oral route is more effective in increasing HDL cholesterol levels, the transdermal route is better for reducing the serum triglyceride level; hence, the latter should be the route of choice in women with high serum triglyceride levels. 相似文献
993.
Success of laparoscopic ovarian wedge resection is related to obesity,lipid profile,and insulin levels 总被引:13,自引:0,他引:13
OBJECTIVE: To evaluate the effects of laparoscopic ovarian wedge resection on hormonal and metabolic parameters of polycystic ovary syndrome (PCOS) and to compare profiles of women who achieved pregnancy with those who did not. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Thirty-three women with PCOS. INTERVENTION(S): Laparoscopic ovarian wedge resection using harmonic scalpel. MAIN OUTCOME MEASURE(S): Pregnancy; levels of testosterone, DHEAS, gonadotropins, sex hormone-binding globulin (SHBG), and glucose and insulin during 2-hour glucose tolerance test; lipid profile; body mass index; and waist-to-hip ratio. RESULT(S): Twenty-two women (67%) achieved clinical pregnancy within the mean of 4.9 months after surgery. Baseline parameters of women who became pregnant differed from those who did not: those who became pregnant were less obese, had lower levels of total cholesterol, low-density lipoprotein, and triglycerides; higher levels of SHBG; lower levels of fasting insulin; lower insulin area under the curve; and higher insulin sensitivity index. Subjects not pregnant by 12 weeks after surgery underwent repeat endocrine and metabolic evaluations. In these women, wedge resection was followed by declines in testosterone, LH, and insulin sensitivity index. Wedge resection had no significant effect on SHBG, DHEAS, or lipid profile. CONCLUSION(S): Laparoscopic wedge resections are associated with the highest pregnancy rates among less obese subjects with favorable lipid profiles and lower insulin. In this study, the postoperative decline of serum testosterone and LH is not attributable to improvement of insulin sensitivity. 相似文献
994.
Rod outer segment membranes (ROS) are highly vulnerable to autooxidation because of their high content of long chain polyunsaturated fatty acids (PUFAs). Melatonin and N-acetylserotonin are indoleamines synthesized in the pineal gland, retina and other tissues. These compounds are free radical scavengers and indirect antioxidants because of their stimulatory effect on antioxidative enzymes. We compared the in vitro protective effect of melatonin and N-acetylserotonin on the ascorbate-Fe2+ induced lipid peroxidation of PUFAs located in ROS membranes. This process was measured by chemiluminescence and fatty acid composition of total lipids of ROS. We assayed increasing concentrations of melatonin (0-10 mm) and N-acetylserotonin (0-2 mm). In both cases the total cpm originated from light emission (chemiluminescence) was found to be lower in those membranes incubated in the presence of either melatonin or N-acetylserotonin; this decreased proportional to the concentration of the indole. Thus, 10 mm melatonin and 2 mm N-acetylserotonin produced a reduction of 51 +/- 6 and 100% in the total chemiluminescene (lipid peroxidation), respectively. We also noticed a PUFAs protection: the docosahexaenoic acid content decreased considerably when the membranes were submitted to oxidative damage. This reduction was from 37.6 +/- 2.1% in the native membranes to 6.2 +/- 0.8% in those which were peroxidized. These changes were less pronounced in treated ROS membranes; as an example in the presence of 10 mm melatonin or 2 mm N-acetylserotonin we observed a content preservation of 22:6 n-3 (23.6 +/- 1.2 and 39.1 +/- 1.2% respectively). The concentration of each compound required to inhibit 50% of the lipid peroxidation (IC50) was 9.82 mm for melatonin and 0.43 mm for N-acetylserotonin, respectively. N-acetylserotonin shows a protective effect about 20 times higher than that of melatonin. 相似文献
995.
Preventive effect of melatonin on the progression of alpha-naphthylisothiocyanate-induced acute liver injury in rats 总被引:1,自引:0,他引:1
The preventive effect of melatonin on the progression of alpha-naphthylisothiocyanate (ANIT)-induced acute liver injury with cholestasis was examined in rats treated once with the hepatotoxin [75 mg/kg body weight (BW), i.p.]. In rats treated with ANIT alone, liver injury with cholestasis occurred 24 hr after treatment and progressed at 48 hr, judging from the serum levels of hepatobiliary marker enzymes and components. Melatonin (10 or 100 mg/kg BW) was orally administered to the ANIT-treated rats, 24 hr after the hepatotoxin treatment at which time hepatic injury had already developed. The administered indoleamine prevented the progression of liver cell damage rather than biliary cell damage more effectively at the higher dose than at the lower dose. In rats treated with ANIT alone, the serum and hepatic concentrations of thiobarbituric acid reactive substances, an index of lipid peroxidation, and the hepatic activity of myeloperoxidase, an index of tissue neutrophil infiltration, increased 24 hr after treatment and further increased at 48 hr. In the liver of rats treated with ANIT alone, Cu,Zn-superoxide dismutase activity decreased 24 hr after treatment and was further reduced at 48 hr, although there was no change in Mn-superoxide dismutase activity. Catalase and Se-glutathione peroxidase activities also decreased at 48 hr, while reduced glutathione concentrations remained increased at 24 and 48 hr. The melatonin administered to the ANIT-treated rats attenuated the increases in serum and hepatic concentrations of thiobarbituric acid reactive substances and the decreases in hepatic activities of Cu,Zn-superoxide dismutase, catalase, and Se-glutathione peroxidase found at 48 hr after the hepatotoxin treatment more effectively at the higher dose than at the lower dose; on the other hand, melatonin treatment had no effect on the increases in hepatic myeloperoxidase activity and reduced glutathione concentration found at 48 h. These results indicate that orally administered melatonin at pharmacological doses prevents the progression of ANIT-induced acute liver injury, mainly liver cell damage, in rats, and suggest that the administered melatonin exerts these preventive effects through its direct and indirect antioxidant actions. 相似文献
996.
The Protective Effects of Monophosphoryl Lipid A on the Ischemic Myocardium and Endothelium in Rats 总被引:3,自引:0,他引:3
Zhu HQ Jiang JL Lu R Zhang XH Deng HW Li YJ 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2003,17(4):311-318
Previous investigations have shown that a single dose of low-density lipoprotein (LDL) injection causes a marked decrease in endothelium-dependent relaxation, and that endothelial dysfunction aggravates myocardial injury due to ischemia-reperfusion in atherosclerotic animals. Monophosphoryl lipid A-induced delayed preconditioning preserves the ischemic myocardium and endothelial cells. The objective of the present study was to examine the effect of monophosphoryl lipid A on endothelial function and ischemia-reperfusion-induced myocardial injury in the rats treated with LDL. A single injection of native LDL (4 mg/kg, i.v.) caused a significant decrease in vasodilator responses to acetylcholine and an increase in the serum level of asymmetric dimethylarginine, the endogenous nitric oxide synthase inhibitor. Pretreatment with monophosphoryl lipid A (300 or 450 g/kg, i.p.) significantly improved endothelium-dependent relaxation and decreased concentrations of asymmetric dimethylarginine, and the effects of monophosphoryl lipid A were attenuated by L-nitro-arginine-methylester, but not by aminoguanidine. LDL treatment only aggravated the decreased coronary flows but did not affect cardiac dysfunction due to ischemia-reperfusion in the rats treated with LDL. Pretreatment with monophosphoryl lipid A significantly improved cardiac dysfunction by ischemia-reperfusion in the rats treated with or without LDL, an effect that was abolished by aminoguanidine. The present study suggests that: (1) a single injection of native LDL causes a decrease in endothelium-dependent relaxation, and aggravates the decrease of coronary flow due to ischemia-reperfusion, (2) pretreatment with monophosphoryl lipid A protects the myocardium against ischemia-reperfusion in the rats treated with or without native LDL, and (3) the protective effect of monophosphoryl lipid A on endothelial cells is related to reduction of asymmetric dimethylarginine level. 相似文献
997.
Serysheva VV Borisova MP Mezhevikina LM Poltavtseva RA Sukhkih GT 《Bulletin of experimental biology and medicine》2002,134(6):534-537
We studied the effect of leukemia-inhibiting factor on bilayer lipid membranes. Leukemia-inhibiting factor in a concentration of 10 ng/ml nonspecifically increased membrane permeability for ions. Leukemia-inhibiting factor acts as a surface-active substance on bilayer lipid membranes. 相似文献
998.
The effect of six polymorphisms in the Apolipoprotein B gene on parameters of lipid metabolism in a Danish population 总被引:2,自引:0,他引:2
Lipoproteins are vehicles for the distribution of plasma lipids and polymorphisms in the genes for apolipoproteins could influence the amount of lipid in plasma. We examined the effect of six single nucleotide polymorphisms in codons 71, 591, 2488, 2712, 3611, and 4154 of the apolipoprotein B gene on fasting levels of triglyceride, VLDL-, LDL-, HDL- and total cholesterol and on body mass index (BMI) in a cohort of 2656 Danes aged 40-70 years using a linear model correcting for the effects of gender, age, BMI, smoking, alcohol consumption and physical activity. The codon 2488 polymorphism was the most influential of the tested polymorphisms, significantly influencing triglyceride (P = 0.002), LDL-cholesterol (P < or = 0.0004), VLDL-cholesterol (P = 0.006) and total cholesterol (P = 0.0001). The codon 2712 polymorphism had an impact on triglyceride (P = 0.007) and VLDL-cholesterol (P = 0.001), while the codon 71 polymorphism influenced LDL- and total cholesterol (P = 0.04 and P = 0.02, respectively). An interaction between smoking and codon 591 (P = 0.03) and smoking and codon 3611 (P = 0.02) on BMI was observed, as well as modest interactions between codon 3611 and codons 2488 and 2712 on lipid parameters. All polymorphisms were in close linkage disequilibrium. The population was not in Hardy-Weinberg equilibrium in four of the six polymorphisms but the lack of equilibrium was restricted mainly to the 60-year olds. 相似文献
999.
Mongan PD Karaian J Van Der Schuur BM Via DK Sharma P 《The Journal of surgical research》2003,112(2):180-188
The inadequate availability of fuel substrates and sharp decline in cellular ATP have been implicated in a cascade of events associated with cell death and organ failure during hemorrhagic shock (HS). In this in vivo swine model of severe prolonged HS, the effect of exogenous pyruvate administration on various markers of cell damage in brain and liver was examined. Thirty minutes after the start of controlled arterial hemorrhage, 30% sodium pyruvate, 10% saline, or 0.9% saline was administered via jugular vein. Four hours after the initiation of hemorrhage, tissue samples from brain and liver were obtained and examined for the cellular and molecular markers of cellular damage. Results of our study suggest that pyruvate prevents loss of total NAD content, cleavage of poly-ADP ribose polymerase (PARP), and inhibits lipid peroxidation in both the brain and liver of swine during prolonged severe HS. We conclude that there are multiple mechanisms by which pyruvate can possibly prevent cell damage caused during HS. 相似文献
1000.
Zeybek N Gorgulu S Yagci G Serdar M Simsek A Kaymakcioglu N Deveci S Ozcelik H Tufan T 《The Journal of surgical research》2003,115(2):286-293
BACKGROUND AND OBJECTIVE: Acute pancreatitis is an important and fatal disease with high mortality and morbidity. Although the pathogenesis of acute pancreatitis is poorly understood, there are many studies that suggest the role for oxygen free radicals (OFRs) in the development of pancreatitis and its complications and show beneficial effects of scavenger treatment. In the present study, we aimed to investigate whether Egb761, the standardized extract of gingko biloba, restrains the generation of OFRs and ameliorates the histopathologic findings of acute pancreatitis. MATERIALS AND METHODS: Sixty male Sprague Dawley rats were randomly assigned to one of the following experimental groups. In early and late pancreatitis and treatment groups, acute pancreatitis was induced by retrograde infusion of 3% sodium taurocholate. In treatment groups, 100 mg/kg Egb 761 was given intraperitoneally (IP) 24 h and immediately before induction of pancreatitis. Sham-operated rats received isotonic saline instead of sodium taurocholate. After observation times of 3.5 and 12 h, the pancreas was removed for light microscopy and determination of malondialdehyde (MDA) levels as a marker for OFRs-induced lipid peroxidation. Serum samples also were obtained for amylase and lipase levels. RESULTS: There was no significant difference in control and sham-operated groups in terms of histopathologic findings and serum enzyme levels. The tissue concentrations of MDA and serum enzyme levels were significantly elevated in early and late treatment groups as compared with the control group. The treatment with Egb 761 caused significant decrease in serum amylase and lipase levels and histopathologic scores as compared with early and late pancreatitis groups. CONCLUSIONS: Prophylactic application of Egb761 exerts highly beneficial influence on the course of acute pancreatitis, and this seems to be related to the oxygen radical scavenger effect of Egb761. 相似文献