The increase in hepatic uncoupling by fenofibrate contributes to a decrease in adipose tissue in obese rats

Fenofibrate is a drug that has been suggested to inhibit weight gain by increasing the catabolism of fatty acid in the hepatic mitochondria. We hypothesized that fenofibrate induces an increase in energy expenditure in the hepatic mitochondria, which results in the reduction of adipose tissue. In this study we measured hepatic uncoupling protein (UCP)-2, -3, core temperatures and abdominal fat composition with MRI in Otsuka Long-Evans Tokushima Fatty rats. The fenofibrate group (n=7) was fed fenofibrate (320 mg/kg) mixed chow. The control group (n=7) was fed chow only. The body weight (531.6+/-7.6 g) of the fenofibrate group was significantly lower than that (744.3+/-14.9 g) of the control group (p<0.005). The areas of visceral and subcutaneous fat in the fenofibrate group (11.0+/-0.9 cm(2), 4.2+/-0.3 cm(2)) were significantly less than those in the control group (21.0+/-0.7 cm(2), 7.4+/-0.4 cm(2)) (p=0.046, respectively). The esophageal and rectal temperatures of the fenofibrate group (37.7+/-0.1 degrees C, 33.1+/-0.2 degrees C) were significantly higher than those of the control group (37.3+/-0.1 degrees C, 32.2+/-0.1 degrees C) (p=0.025, p=0.005). There was de novo expression of UCP-3 in the liver of the fenofibrate group. These data suggest that increased energy dissipation, via hepatic UCP-3 by fenofibrate, contribute to decreased weight gain in obese rats.     

Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: Case studies with fenofibrate

The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (∼70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65–72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.     

非诺贝特双层渗透泵片在Beagle犬体内的药动学研究

目的 研究非诺贝特双层渗透泵片在犬体内的药动学特征,并评价受试制剂和参比制剂的生物等效性。方法 采用LC-MS测定比格犬体内的血药浓度,采用DAS 2.1.1软件计算药动学参数。结果 受试制剂和参比制剂血浆中非诺贝特酸的Cmax分别为（1 100.0±771.2）、（924.3±564.0）ng/mL,tmax分别为（6.7±8.5）、（2.5±0.5）h,AUC0-t分别为（17 841.1±12 220.7）、（17 615.5±12 870.2）ng·h/mL;t1/2分别为（17.7±8.2）、（16.4±3.3）h,MRT0-t分别为（24.7±4.0）、（24.5±5.2）h,受试制剂中非诺贝特酸的平均相对生物利用度为（104.7±12.4）%。结论 受试制剂非诺贝特渗透泵片和参比制剂非诺贝特缓释胶囊具有生物等效性。     

HPLC法测定非诺贝特缓释片中非诺贝特

目的采用HPLC法测定非诺贝特缓释片中非诺贝特。方法采用DikmaC18色谱柱（200mm）〈4．6mm,5μm）;流动相：甲醇-水（90：10）;检测波长：288nm;柱温：25℃;体积流量：1．0μL／mim进样量10μL。结果非诺贝特在2．0～12．0μg／mL与其峰面积呈良好的线性关系（F=0．9999）;检测限和定量限分别为10、30ng／mL;平均回收率为99．86％,RSD值为0．72％（n=9）。结论该方法准确、简便,可用于非诺贝特缓释片中非诺贝特的质量控制。     

非诺贝特PEG2000-DSPE胶束的制备及在大鼠体内的口服药动学研究

目的:为提高非诺贝特溶解度,将非诺贝特包载于PEG₂₀₀₀-DSPE胶束中,研究其在SD大鼠体内的口服药动学情况。方法:对非诺贝特PEG₂₀₀₀-DSPE胶束进行表征,大鼠单剂量灌胃给予非诺贝特PEG₂₀₀₀-DSPE胶束和非诺贝特混悬液,眼底静脉丛取血,HPLC法测定血浆中非诺贝特酸含量,并用药物与统计（Drug and Statistics,DAS）软件分析处理药动学数据。结果:成功制备了非诺贝特PEG₂₀₀₀-DSPE胶束,平均粒径为（23.40±3.62）nm,包封率和载药量分别为（97.65±3.32）%和（1.33±0.32）%。大鼠体内口服药动学结果表明非诺贝特PEG₂₀₀₀-DSPE胶束和非诺贝特混悬液的药动学行为均符合二室模型,非诺贝特PEG20 00-DSPE胶束和非诺贝特混悬液的AUC_（0-24）分别为（61.41±5.71）μg·h·ml^-1和（8.49±0.66）μg·h·ml^-1,C_max分别为（9.67±1.65）μg·ml^-1和（0.71±0.09）μg·ml^-1。非诺贝特PEG₂₀₀₀-DSPE胶束的AUC_（0-24）和C_max相比于非诺贝特混悬液组分别提高了7倍和14倍。非诺贝特PEG₂₀₀₀-DSPE胶束相对于原料药生物利用度为723.3%。结论:非诺贝特PEG₂₀₀₀-DSPE胶束显著提高了非诺贝特在大鼠体内的口服吸收速度和生物利用度。PEG₂₀₀₀-DSPE胶束作为口服药物载体具有优良的应用前景。     

正交实验法优选非诺贝特滴丸的处方工艺

目的:以水溶性高分子材料PEG 4000为主要基质,研究非诺贝特滴丸的最佳制血工艺条件。方法:以滴丸的成型率(%)为筛选指标,以滴丸滴制过程的滴速、冷却液面至滴头距离及滴头口径为考察因素,采用正交设计对非诺贝特滴丸的制血工艺进行优选。结果:非诺贝特滴丸的处方工艺,PEG 4000和泊洛沙姆(1:1),在滴制过程中的滴速为45d/min,滴头至冷却液面距离为5cm,滴头内径为5mm,按此优化条件制血的非诺贝特滴丸成型率最高。结论:初步确定了非诺贝特滴丸的处方组成及制血工艺,为提高非诺贝特滴丸制剂的进一步稳定性考察提供参考。     

非诺贝特对脂肪变性肝细胞甘油三酯代谢及氧化应激水平的影响

目的探讨非诺贝特（fenofibrate,FF）对脂肪变性肝细胞甘油三酯代谢及氧化应激水平的影响。方法以油酸（OA）诱导人肝癌HepG2细胞脂肪变性为模型,采用不同浓度的FF（0、5、10、50μmol/L）干预HepG2细胞24h,油红O染色观察HepG2细胞内脂滴,甘油-3-磷酸氧化酶法检测细胞内甘油三酯（TG）含量,硫代巴比妥酸比色法、黄嘌呤氧化酶法分别测定细胞培养上清液中的丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性。结果 OA诱导HepG2细胞脂肪变性,细胞内TG含量明显增加,同时细胞培养上清液中MDA含量增加,SOD活性降低;FF能明显减轻油酸诱导的HepG2细胞脂肪变性,降低细胞内TG水平及细胞培养上清液中MDA含量,提高SOD活性。结论非诺贝特抑制油酸诱导的HepG2细胞脂肪变性,其可能与提高HepG2细胞的抗氧化能力、减轻细胞氧化应激损害有关。     

非诺贝特和吡格列酮联合应用对代谢综合征患者动脉粥样硬化的影响

目的：探讨非诺贝特和吡格列酮联合应用对于代谢综合征患者动脉粥样硬化的影响。方法242例代谢综合症患者分层随机编入基础治疗组（n=64）,非诺贝特组（n=65）,吡格列酮组（n=63）,非诺贝特＋吡格列酮组（联合应用组,n=64）。双盲方法对所有患者均进行生活方式干预及应用相应药物控制血压的基础上,基础治疗组加服安慰剂,非诺贝特组加服非诺贝特0.2 g/次,每日一次,睡前服;吡格列酮组加服吡格列酮15 mg/次,每日一次;联合应用组按上述用药加服上述两种药物,共干预24周。干预前后采用颈动脉超声观察其颈总动脉内膜中层厚度（IMT）和斑块阳性率,采用酶联免疫吸附法（ELISA）测定血清MMP-9浓度。结果干预后联合应用组与非诺贝特组比较,颈动脉IMT及斑块阳性率均降低,差异有统计学意义,P0.05。联合应用组与非诺贝特组和比格列酮组相比,MMP-9浓度下降有显著性差异, P〈0.01。结论非诺贝特和吡格列酮联合应用比单用对于代谢综合征患者动脉粥样硬化有更好的改善作用。     

非诺贝特对高TG的2型糖尿病患者PCI术后的影响

目的通过前瞻性随机对比研究,观察非诺贝特联合阿托伐他汀对高TG的2型糖尿病患者药物洗脱支架置入术后的临床疗效。方法入选符合本研究标准的522例药物洗脱支架置入术后高TG的2型糖尿病患者,随机分为两组,联合治疗组249例,非诺贝特200mg晨日一次口服,阿托伐他汀20mg晚日一次口服;阿托伐他汀组273例,20mg晚日一次口服。疗程12个月。比较两组主要不良心血管事件发生情况、降脂疗效及安全性。结果非诺贝特联合阿托伐他汀组主要不良心血管事件发生率及血清TG明显低于阿托伐他汀组(P<0.05),而HDL-C明显高于阿托伐他汀组(P<0.05)。不良反应发生率相似。结论非诺贝特联合阿托伐他汀明显改善高TG的2型糖尿病患者药物洗脱支架置入术后的预后,两药联合安全有效。     

非诺贝特联合他汀治疗200例经他汀调脂后的高三酰甘油血症的疗效和安全性观察

目的探讨非诺贝特治疗他汀调脂后的高三酰甘油(TG)血症临床效果。方法随机选择2008年11月至2010年4月门诊接受他汀调脂后的高TG患者200例,入选时已服用他汀类药物常规剂量≥3个月,晨口服非诺贝特100mg,晚继续口服原他汀类药物,每晚1次。结果联合用药后总胆固醇(TC)从(6.11±1.15)mmol/L下降至(5.20±0.82)mmol/L;低密度脂蛋白胆固醇(LDL-C)从(3.73±0.76)mmol/L下降至(3.17±0.31)mmol/L;TG从(2.90±0.49)mmol/L下降至(1.46+0.29)mmol/L;高密度脂蛋白胆固醇(HDL-C)从(0.89±0.28)mmol/L升高至(1.26±0.19)mmol/L;治疗前后比较P<0.05,差异均有统计学意义。治疗效果为显效197例,好转3例,无效0例,总有效率为100%(200/200)。治疗中有2例发生胃肠道反应,1例出现转氨酶升高,停药后恢复正常,肝、肾功能均正常,无肌痛发生。结论非诺贝特联合他汀治疗经他汀类调脂后的高TG血症疗效确切且具有良好的安全性。