Hypolipidemic Activity of o-(N-Phthalimido)acetophenone in Sprague Dawley Rats

o-(N-Phthalimido)acetophenone has proven to be an effective hypolipidemic agent in rats at 20 mg/kg/ day orally. The agent suppressed the activity of the rate-limiting enzyme of the liver involved in de novo synthesis of triglycerides. The synthetic rate-limiting enzyme for cholesterol esters was also inhibited by the drug in vivo. o-(N-Phthalimido)acetophenone lowered cholesterol in the liver and the aorta wall and generally caused an increase in phospholipids in body tissues. Serum lipoproteins were modulated by the drug with a decrease in cholesterol and triglycerides in the chylomicron, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) and an increase in high-density lipoprotein (HDL) cholesterol. The phospholipid content was increased in the chylomicron, VLDL, and LDL fractions. In hyperlipidemic rats, o-(N-phthalimido)acetophenone lowered elevated blood lipid levels at 20 mg/kg/day orally after 3 weeks of administration. The hypolipidemic rat after drug treatment had a lower LDL cholesterol and a higher HDL cholesterol content, which is therapeutically desirable to protect against cardiovascular disease.     

The Effects of Phthalimide and Saccharin Derivatives on Low-Density Lipoprotein (LDL) and High-Density Lipoprotein (HDL) Receptor Activity and Related Enzyme Activities

The hypolipidemic agents, phthalimide, saccharin, o-(N-phthalimido) acetophenone, N-(p-chlorobenzoyl) sulfamate, and o-chlorobenzylsulfonamide affected low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptor activity and lipoprotein degradation. In isolated rat hepatocytes, rat aorta foam cells, and human fibroblasts, LDL receptor activity, which is dependent on apo-B and -E, was inhibited by the drugs in a dose-dependent manner. LDL degradation was accelerated in the hepatocytes, while it was inhibited in aorta cells and fibroblasts. The drugs enhanced HDL receptor activity, dependent on apo-E and -Al, and HDL degradation in the hepatocytes, whereas in fibroblasts and aorta cells HDL receptor binding and degradation were suppressed. In parallel, activities of acyl Co A acyl transferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced lipoprotein lipase decreased and activities of HMG–CoA reductase and cholesterol oleate-ester hydrolase increased. In fibroblasts the presence of drugs enhanced HDL binding of intracellular cholesterol. In vivo studies demonstrated that phthalimide and saccharin treatment enhanced the clearance of HDL and decreased the clearance of LDL from the serum of rats. The results suggest that the mode of action of the agents is to modulate the lipoprotein receptor and, thereby, the clearance of lipids from peripheral tissue as part of the hypolipidemic activity.     

The Hypolipidemic Activity of l-N-3-Methylphthalimido-butan-3-semicarbazone in Rodents

l-N-(3-Methylphthalimido)butan-3-one semicarbazone demonstrated potent hypolipidemic activity in normal rats and mice and hyperlipidemic diet-induced mice. The compound decreased tissue lipid levels and increased the fecal excretion of cholesterol and triglycerides. After 2 weeks of administration, serum lipoprotein levels were modulated so that very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol concentrations were reduced and high-density lipoprotein (HDL) cholesterol concentrations were elevated to levels unprecedented by the cyclic imide derivatives previously tested. The VLDL triglyceride content was also reduced. Hepatic in vitro enzymatic studies demonstrated that the compound suppressed the activity of enzymes in the early synthesis of fatty acids and cholesterol and the regulatory enzymes for the de novo synthesis of triglycerides.     

高密度脂蛋白组成部分中的不同亚类对冠状动脉狭窄程度影响的相关性研究

目的：探讨冠脉造影患者高密度脂蛋白（high-density lipoprotein,HDL）亚类对冠状动脉狭窄程度影响的相关性。方法（1）抽取2013—2014年因疑诊冠心病（coronary heart disease,CHD）入住该院老年医学科、心内科行冠状动脉造影（coronary arteriography,CAG）的患者122例,经选择性冠状动脉造影确诊为CHD患者（至少有一支冠状动脉或分支狭窄＞50％）96例,其中男62例,女34例,平均年龄（60．31±8．72）岁,未诊断CHD患者26例,男10例,女16例,平均年龄（59．00±13．51）岁;（2）抽取患者空腹12 h静脉血,选择双向电泳—免疫印迹检测法24 h内测定HDL亚类,对患者冠脉造影结果（采用Gensini评分）评价冠状动脉狭窄程度;（3）计量资料用均数±标准差（x ±s）表示,定性资料用χ2检验,两组比较采用独立样本的t检验, Logisitic回归分析检验与冠心病相关因素,两因素相关性采用线性相关分析。结果（1）单因素卡方、两样本独立t检验显示性别、吸烟史、糖尿病史、收缩压、体质指数（body mass index,BMI）、腰围（waist circumference,WC）、腰臀比（waist to hip ratio, WHR）、HDL、LDL、ApoA-I 、Lpa、Preβ1-HDL、HDL3b、HDL3c、HDL2b与冠心病有关,差异有统计学意义（P＜0．05）;（2）TG、Preβ1-HDL、HDL3b是冠心病危险因素,HDL2b是冠心病保护因素（P＜0．05）;（3）HDL2b与Gensini评分结果成负相关,Preβ1-HDL、HDL3b与Gensini评分结果成正相关。结论在临床诊断治疗中,HDL2b值有可能做为冠心病预测因素,Preβ1-HDL、HDL3b值可为预测和诊断CHD提供重要依据,冠心病的防治不仅要改善和促进胆固醇逆转运还要调节血脂,调整HDL亚类的构成比。     

脂蛋白（a）在动脉粥样硬化患者中的变化及血脂康干预的影响

目的：探讨冠心病（CHD）患者及脑梗死患者血清脂蛋白（a）[Lp(a)]水平及药物干预的影响。方法：151例CHD病人，其中急民生心肌梗死（AMI）20例，陈旧性心肌梗死（OMI）49例，心绞痛（AP）82例；脑梗死患者42例及正常对照组30例，测定其血清Lp(a)浓度。对高Lp(a）水平随机分组用血脂康胶囊及维生素C治疗。结果：CHD及脑梗死组其血清Lp(a)水平明显高于对照组（均P＜0.01)；CHD组高于脑梗死组（P＜0.01)。CHD组中，AMI组＞AP组＞OMI组（P＜0.01或P＜0.05）。用血脂康胶囊4粒/日治疗40例，12周末血清Lp(a)下降19.66%，与治疗前比较差异显著（P＜0.05)。结论：提示Lp(a)有致动脉粥样硬化的作用；血脂康胶囊对高血清Lp(a)水平安全有效。     

The hypolipidemic activity of N(4-methyl-phenyl)diphenimide in rodents

N(4-Methyl-phenyl)diphenimide afforded potent hypolipidemic activity in rodents. Serum cholesterol levels were reduced 67% and serum triglyceride were lowered 66% in rats by the drug after two weeks administration orally at 20 mg/kg/day. Rate limiting enzymes in the de novo synthesis of lipids in the liver were suppressed by the drug. Cholesterol was also removed from the body due to the drug accelerating bile excretion. Lipids removed from the blood compartment were not deposited in the organs of the body. VLDL and LDL cholesterol content was significantly reduced in rats treated with the drug with marked increase in HDL cholesterol after two weeks of administration. These data suggest that the drug may be useful in hyperlipidemic states and atherosclerosis in man, thus, further investigation of this class of chemicals is warranted.     

Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration

1. Tris(4-chlorophenyl)methane (TCPME) and tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues.

2. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice.

3. [¹⁴C]TCPME was well absorbed (≥66%) in male rats and mice following a single oral administration of 1, 10, or 100?mg/kg. The excretion of [¹⁴C]TCPME-derived radioactivity in urine (≤2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥?64%) with adipose containing the highest concentrations. The metabolism of TCPME was minimal. The disposition and metabolism of [¹⁴C]TCPME in females was similar to males.

4. The time to reach maximum concentration was ≤7?h, the plasma elimination half-life was ≥31?h, and the bioavailability was ≥82% following a 10?mg/kg oral dose of [¹⁴C]TCPME in male rats and mice.

5. The disposition of [¹⁴C]TCPMOH was similar to that of [¹⁴C]TCPME.

6. Following an intravenous administration of [¹⁴C]TCPME or [¹⁴C]TCPMOH in male rats and mice, the pattern of disposition was similar to that of oral administration.

7. In conclusion, both TCPME and TCPMOH are readily absorbed and highly bioavailable following a single oral administration pointing to importance of assessing the toxicity of these chemicals.

     

Exendin-4对糖尿病大鼠糖脂代谢的影响

目的:观察Exendin-4对2型糖尿病(T2DM)大鼠糖脂代谢及胃排空的影响。方法:高脂高糖饲料加小剂量链脲佐菌素制备T2DM大鼠模型,随机分为正常对照组(NC组)、正常干预组(NE组)、糖尿病对照组(DC组)和糖尿病干预组(DE组);Exendin-4(2ng/g,2次/d)干预50d。核素法测定各组大鼠胃半排时间、排空速率,留取血清测定空腹血糖(FBG)、糖化血清蛋白(GSP)、游离脂肪酸(FFA)、总胆固醇(TC)和三酰甘油(TG)的含量。结果:DC组较NC组FBG、GSP、FFA、TC和TG水平升高,胃半排时间缩短、排空速率加快,差异有统计学意义(P<0.05或P<0.01)。DE组较DC组FBG、GSP和FFA浓度降低,胃半排时间加长、而排空速率减慢,差异有统计学意义(P<0.05或P<0.01)。多因素逐步回归分析示影响胃半排时间的因素是FBG。结论:Exendin-4可以改善同期糖尿病大鼠的血糖、FFA及胃排空异常。     

胆固醇酯转移蛋白抑制剂Anacetrapib

高密度脂蛋白-胆固醇(HDL-C)低于正常水平是诱发心血管疾病的因素之一,升高较低水平的HDL-C能够降低患心血管疾病的风险.一些代谢疾病,如胰岛素耐受、高三酰甘油血症都会增强胆固醇酯转移蛋白的活性,高活性的胆固醇酯转移蛋白可诱发动脉粥样硬化和增加患心血管疾病的风险.因此,抑制胆固醇酯转移蛋白是治疗动脉粥样硬化症的新靶...     

苯溴马隆对高尿酸血症模型大鼠脂质代谢的影响

目的 基于脂质组学方法研究苯溴马隆治疗高尿酸血症（hyperuricemia,HUA）大鼠的作用机制,并揭示尿酸水平增高与脂质代谢异常的内在相关性。方法 利用超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF/MS）技术,结合主成分分析（PCA）和偏最小二乘法判别分析（OPLS-DA）研究正常组、模型组和苯溴马隆组的大鼠血清中内源性脂质代谢物的变化,寻找潜在生物标记物,分析相关代谢通路,绘制代谢网络机制图。结果 脂质组学分析发现,苯溴马隆可使HUA大鼠体内水平异常的20个差异代谢物回调到正常水平;相关代谢通路分析发现,苯溴马隆影响果糖诱导HUA大鼠血清中的脂质水平,主要与甘油磷脂代谢通路相关。结论 苯溴马隆对HUA的治疗可能与改善体内甘油磷脂代谢通路异常密切相关。     

The Hypolipidemic Effects of l-Acetyl-4-phenyl-l,2,4-triazolidine-3,5-dione in Rodents

l-Acetyl-4-phenyl-l ,2,4-triazolidine,5-dione (APTD), a potent hypolipidemic agent, lowered both serum cholesterol and triglyceride levels in normo- and hyperlipidemic rats at 10 or 20 mg/kg/day. The agent effectively lowered VLDL-cholesterol (VLDL-C) and LDL-C content and raised HDL-C content in normal and hyperlipidemic rats treated from 4 to 8 weeks. Similar effects on the incorporation of cholesterol into the lipoprotein fractions were observed after drug treatment. Tissue lipids, e.g. cholesterol, were lowered, whereas fecal cholesterol levels were increased. APTD's primary targets were acyl CoA cholesterol acyl transferase (ACAT) for cholesterol ester synthesis and sn-glycerol-3-phosphate acyl transferase (GPAT) and phosphatidylate phosphohydrolase (PPH) for triglyceride synthesis.     

铬(Ⅲ)配合物治疗高脂蛋白血症95例

本文报道用铬(Ⅲ)配合物治疗各型高脂蛋白血症95例的临床疗效。采用自身单盲前后对照观察,先服安慰剂1.5mo,继服本药5mg bid 1.5mo。血清总胆固醇增高者42例,治疗后平均下降0.7mmol/1,总有效率65％。甘油三酯增高者89例,平均下降1.4 mmol/1,总有效率74％。治疗后各项血脂水平改变与服安慰剂后相比有非常显著性差异(P<0.01)。治前同时血糖增高者,亦有明显下降,平均下降0.74 mmol/1。血液流变学指标亦有不同程度的改善。治疗中未发现有毒副反应。本药为一种治疗脂质及糖代谢紊乱的有效药物,值得进一步研究。     

高血压合并脂代谢紊乱对颈动脉重构的影响

目的:观察伴有或不伴有血脂代谢紊乱的高血压患者的颈动脉内膜-中膜厚度(IMT)和颈动脉内径、扩张性及僵硬度,探讨血脂在高血压患者颈动脉重构中的作用.方法:入选对象172例,其中正常对照组50例,高血压血脂正常组62例,高血压血脂紊乱组60例,未服用过他汀类、贝特类及烟酸等调脂药物.通过颈动脉超声测定颈动脉IMT和内径,并计算颈动脉扩张性及颈动脉僵硬度.结果:IMT、内径、僵硬度高血压血脂正常组显著高于正常对照组(P＜0.05),高血压血脂紊乱组则高于高血压血脂正常组(P＜0.05).颈动脉扩张性高血压血脂正常组较正常对照组显著降低(P＜0.05),高血压血脂紊乱组较高血压血脂正常组也显著降低(P＜0.05).低密度脂蛋白胆固醇(LDL-C)与颈动脉IMT(r=0.318,P＜0.01)、内径(r=0.333,P＜0.01)呈正相关,高密度脂蛋白胆固醇(HDL-C)与颈动脉IMT及内径无明显相关(r分别为0.038和0.078,均P＞0.05).结论:高血压合并血脂紊乱可对颈动脉重构起到促进作用,其中LDL-C升高型血脂代谢紊乱影响更为显著,而HDL-C与颈动脉重构无明显相关.     

Toxicological studies on 4-(hexadecylamino)benzoate (PHB), an agent with anti-atherosclerotic properties,in the rat

The subacute oral toxicity of sodium 4-(hexadecylamino)benzoate (PHB) was studied in male and female Sprague-Dawley rats. The animals were given PHB 0, 10, 30, 100 or 300 $\text{mg}\text{kg}$ body weight as a 3% gum arabic suspension for 13 weeks. During PHB administration all animals on the highest dose level died or were killed because of loss of weight: there were deaths also in the 100 $\text{mg}\text{kg}$ group. PHB caused a leukocytopenia which was significant only at the highest dose level. The hemoglobin decreased in the two lowest dose groups. In the highest dose group the histological liver pictures were pathological. Acidophilic bodies and karyorrhexis indicating severe liver cell damage occurred at this level. In the groups receiving 30, 100 and 300 $\text{mg}\text{kg}$ there were foci with poorly distinguishable liver cells, mono-nuclear cells and some neutrophiles. PHB had no noticeable toxic effects on the other organs or parameters measured.     

Toxicokinetic Study of Recombinant Human Heparin-Binding Epidermal Growth Factor-Like Growth Factor (rhHB-EGF) in Female Sprague Dawley Rats

Purpose To determine the toxicity and pharmacokinetics of recombinant heparin-binding epidermal growth factor-like growth factor in female Sprague Dawley rats following intra-bladder and intravenous administration. Materials and Methods rhHB-EGF was administered once daily for 6 or 27 days at doses of 3, 10, or 30 μg/kg. ¹²⁵I-rhHB-EGF was administered on day 7 or 28 for pharmacokinetic analysis. Toxicity was assessed by general appearance and behavior, gross necropsy, blood chemistry and microscopic evaluation. Results Plasma AUCss of [¹²⁵I] rhHB-EGF equivalents following IB administration for 7 days were 4.28 ± 2.29, 7.75 ± 2.70, and 7.11 ± 1.42 ng ml⁻¹ h⁻¹ at doses of 3, 10, and 30 μg/kg, respectively. Following IV administration, the AUCss on day 7 increased from 27.0 ± 2.66 to 124 ± 5.09 and 385.11 ± 7.57 ng ml⁻¹ h⁻¹ with increasing the dose from 3 to 10 and 30 μg/kg. Similar AUCss data was obtained after 28 day administration. No toxicity was evident upon gross examination. Histologic examination revealed subacute inflammation and lymphocytic infiltration of the urinary bladder in animals from all groups dosed by the IB route. Conclusions Plasma and bladder concentrations of recombinant human [¹²⁵I] rhHB-EGF equivalents were significantly lower following the IB route than following IV administration. Histologic tissue examination indicated no toxicity attributable to rhHB-EGF.     

Characterization of calcitonin gene-related peptide(CGRP) receptors in intramural coronary arteries from male and female Sprague Dawley rats

1. In this study we characterized the CGRP-receptor subtype by Schild-plot analysis using the C-terminal fragment, human-αCGRP(8–37), a putative competitive CGRP₁-receptor selective antagonist. In addition, the effect of rat-αCGRP was compared with that of homologous peptides rat-βCGRP, rat-amylin, rat-adrenomedullin and [Cys(Acm)^2,7]-human-αCGRP, a putative selective CGRP₂-receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats.
2. Isolated rings from the distal, intramural part of the left anterior descending (LAD) coronary artery in both groups of rats were mounted on a double wire-myograph. The arteries were then stretched to their optimal lumen diameter for active tension development and precontracted with 10⁻⁵ M prostaglandin F_2α (PGF_2α), after which agonists were added to the organ bath in a cumulative manner.
3. Rat-αCGRP induced endothelium-independent relaxations in male and female Sprague-Dawley rats. Rat-βCGRP concentration-response relations (10⁻¹¹–10⁻⁷ M) were similar to those of rat-αCGRP in either sex. The maximal relaxations induced by rat-amylin and rat-adrenomedullin, both at 10⁻⁶ M, were significantly (P<0.05) lower than those induced by rat-α- and rat-βCGRP. In contrast, the selective CGRP₂-receptor agonist [Cys(Acm)^2,7]-human-αCGRP failed to induce significant relaxations at the highest concentration used (10⁻⁷ M) in the coronary arteries of male and female rats.
4. The C-terminal fragment, human-αCGRP(8–37) blocked concentration-dependently (10⁻⁷–10⁻⁶ M) the rat-αCGRP-induced relaxation in 10⁻⁵ M PGF_2α-precontracted coronary arteries. The slopes of the regression lines of the Schild-plots for both male and female rats were not significantly (P>0.05) different from unity and the pA₂ values for human-αCGRP(8–37) were 6.93 and 6.98 in arteries from male and female rats, respectively. There was no significant (P>0.05) difference in estimated pK_B values for human-αCGRP(8–37) between male (6.99±0.10, n=13) and female (6.95±0.08, n=13) rats.
5. The concentration-response relationships for rat-α- and rat-βCGRP were similar in male and female Sprague Dawley rats. The predominant CGRP receptor subtype in small intramural coronary arteries appeared to belong to the CGRP₁-receptor subtype in both sexes.

     

Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia

ABSTRACT

Background: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia.

Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment.

Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL?C) and non-high-density lipoprotein cholesterol (HDL?C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL?C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concen­trations of dense LDL subfractions was observed. Patients with triglyceride values >1.7?mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL?C mainly due to a fall in the concentration of dense HDL subfractions.

Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles.     

太子参多糖对糖尿病大鼠糖、脂代谢的影响

目的观察太子参多糖对糖尿病大鼠糖、脂代谢的影响。方法大鼠腹腔注射四氧嘧啶200mg／kg制作糖尿病模型,观察太子参多糖不同剂量（1．2,0．6,0．3g／kg）对实验性糖尿病大鼠空腹血糖、血脂、胰岛素水平的影响。结果太子参多糖能改善糖尿病大鼠的一般状况,延缓体重下降,降低空腹血糖,降低甘油三酯（TG）和总胆回醇（TC）水平,但不影响胰岛素水平。结论太子参多糖对糖尿病大鼠有显著治疗作用。     

复方苦豆子颗粒对高脂血症大鼠血脂代谢的影响

目的:观察复方苦豆子颗粒对高脂血症大鼠血脂代谢的影响。方法:除空白对照组外,用喂饲高脂饲料法复制大鼠高脂模型,实验分空白对照组、高脂模型组、复方苦豆子颗粒组(低、中、高剂量组,分别喂饲生药7g.kg-1.d-1、15g.kg-1.d-1、22g.kg-1.d-1)、血脂康组(0.8g.kg-1.d-1),给药后每4wk抽1次血,连续3次,分别测定血浆总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、极低密度脂蛋白胆固醇(VLDL-C)、高密度脂蛋白胆固醇(HDL-C)、丙二醛(MDA)含量变化。结果:高脂模型组血浆TC、TG、LDL-C、VLDL-C、HDL-C和MDA含量显著上升,同时动脉粥样硬化指数(AI)增加;给予复方苦豆子颗粒4wk后,各组血浆TC、TG、LDL-C、VLDL-C、MDA及AI水平均降低,且呈剂量依赖性。结论:复方苦豆子颗粒对高脂血症大鼠具有调血脂作用。     

3种非典型抗精神病药物对精神分裂症患者脂代谢的影响

目的探讨利培酮、阿立派唑和齐拉西酮3种非典型抗精神病药物对精神分裂症患者脂代谢的影响。方法将270例精神分裂症患者随机分成3组,测定单药治疗前后8周空腹血脂,观察治疗前后体质量和腰围。结果利培酮、阿立哌唑、齐拉西酮对脂代谢均有影响。其中体质量、腰围、总胆固醇、低密度脂蛋白升高与治疗前相比有显著性差异(P<0.01)。结论非典型抗精神病药物中利培酮、阿立哌唑和齐拉西酮对脂代谢均有明显影响。