肉碱和长链脂肪醇对小鼠大脑乙酰胆碱的影响

目的　探讨肉碱和长链脂肪醇对小鼠大脑乙酰胆碱 (Ach)含量的影响。方法　用析因实验设计方法将BALB/C成年雄性小鼠随机分为标准对照、高脂对照、肉碱、长链脂肪醇、肉碱和长链脂肪醇合用共 5组 ,标准对照组饲标准饲料 ,其它各组饲含 2 0 %油脂的饲料 ,肉碱 [剂量 50mg/ (kg·鼠重 ) ]和长链脂肪醇 [剂量 50mg/ (kg·鼠重 ) ]以0 0 9%的剂量加到饲料中连续喂养 3 0d后 ,称体重、脑重 ,计算脑体比 ,用碱性羟胺比色法测大脑组织中Ach含量。结果　肉碱和长链脂肪醇对成鼠体重、脑重、脑体比无显著影响 (P >0 0 5) ;高脂饲料组小鼠脑内Ach含量较对照组明显降低 (P <0 0 5) ,长链脂肪醇可引起高脂动物脑内Ach含量升高 (P <0 0 5) ,但与正常饲料组无明显差异 (P >0 0 5) ;肉碱引起脑内Ach含量明显增多 (P <0 0 5) ;但两者联合作用时有交互作用 (P <0 0 1) ,且脑内Ach含量约等于者单独作用的差值。结论　肉碱、长链脂肪醇能分别促进小鼠大脑Ach含量的增加 ,但联合作用时表现为拮抗     

毛细管气相色谱法测定多廿醇片中5种主要成分的含量

目的:建立毛细管气相色谱法直接测定多廿醇片中5种主要成分(二十四烷醇、二十六烷醇、二十七烷醇、二十八烷醇和三十烷醇)的含量。方法:采用 Agilent 4890D 气相色谱仪,氢火焰离子检测器,DB-5HT(30 m×0.25 mm,0.1μm)毛细管色谱柱。初始温度120℃保持5 min,然后以20℃·min~(-1)速度升至270℃保持1 min,再以5℃·min~(-1)升温至310℃保持5min。用正二十烷醇作内标物定量,进样量1μL(分流比6:1)。结果:多廿醇在4.8～432.0μg·mL~(-1)考察范围内,各组分峰面积与内标峰面积的比值与其对应的浓度呈良好的线性关系,r 值均大于等于0.9996,最低检出限为3μg·mL~(-1)。方法回收率在96.8%～101.2%之间,RSD 在0.29%～3.7%。结论:本法操作简单、准确,重复性、稳定性好,结果准确可靠,是一种可行的多廿醇含量测定方法。     

胆固醇酯转运蛋白基因TaqⅠ多态性与多廿烷醇降脂疗效的关系

目的:了解胆固醇酯转运蛋白(CETP)TaqⅠ基因多态性与新型降脂药物多廿烷醇(policosanol)疗效的关系。方法:入选54例LDL-C≥3.62 mmol.L-1,或TC≥6.2 mmol.L-1汉族原发性高胆固醇血症患者,服用10mg.d-1多廿烷醇12周,于0周和12周进行血脂检查;同时进行CETP TaqI位点多态性检测(PCR-RFLP方法)。结果:CETP基因TaqI位点B1B1,B1B2,B2B2基因型频率分别是31.48%,44.44%,24.07%。0周时apoA水平在3种基因型呈B1B1相似文献   

新型调脂药普利醇的药理和临床研究

普利醇(policosanol)是从甘蔗蜡中提取的高相对分子质量脂肪醇混合物,是一种与他汀类不同的新型调脂药,其主要成分是二十八烷醇。它可有效降低血清胆固醇水平,抑制血小板凝聚,抑制血管内皮平滑肌细胞的增生,且安全性和耐受性好。目前已在古巴和其他南美国家上市。现对普利醇的药动学、药效学、毒理学、临床研究和药物相互作用等方面作一综述。     

A randomized, double-blind, placebo-controlled study of the efficacy and tolerability of policosanol in adolescents with type II hypercholesterolemia

Background: Atherosclerosis begins in childhood and is influenced by risk factors for coronary heart disease (CHD), of which hypercholesterolemia is crucial. The rationale for treating hypercholesterolemia in childhood is to limit atherosclerosis development, for which adherence to a cholesterol-lowering diet is the first-choice therapy. Nevertheless, pharmacological intervention with bile acid-binding resins may be prescribed for patients older than 10 years, mainly those with family history of CHD, multiple risk factors, and/or severe hypercholesterolemia. Resins are effective and tolerable in this population, but their clinical use has been limited because of poor compliance due to unpalatability; other effective cholesterol-lowering drugs have not been recommended in this population because of the potential impact of drug-related adverse effects such as increases in transaminases, myopathies, and gastrointestinal disturbances. Thus, the need for safer, easy-to-take, and effective cholesterol-lowering agents for this population continues. Policosanol is a mixture of higher primary aliphatic alcohols purified from sugar cane wax with cholesterol-lowering effects proven in patients with type II hypercholesterolemia and dyslipidemia due to type 2 diabetes mellitus. Policosanol shows good safety and tolerability profiles, with no evidence of drug-related adverse events (AEs) to date. This background supports the idea that policosanol could be a good candidate for treating hypercholesterolemia in children and adolescents, but it requires clinical demonstration.Objective: This 12-week study was undertaken to investigate the cholesterol-lowering effects and tolerability of policosanol in hypercholesterolemic patients aged 11 to 19 years.Methods: In this randomized, double-blind, placebo-controlled study, after 4 weeks of dietary stabilization, adolescents with type II hypercholesterolemia were randomly assigned (1:1 ratio) to receive placebo or policosanol 5-mg tablets once daily for 12 weeks. Physical examinations were performed, and lipid profiles and blood samples were obtained at baseline and after 6 and 12 weeks of therapy. The treatment was considered effective if mean reductions of low-density lipoprotein cholesterol (LDL-C) were >15%. In addition, the percentages of patients reaching final values of LDL-C <3.4 mmol/L and optimal values of <2.8 mmol/L were also evaluated. The doses were doubled if LDL-C values were ≥3.4 mmol/L after 6 weeks of therapy. The incidence of AEs and compliance with study medications were also evaluated after 6 and 12 weeks of treatment.Results: Fifty-five patients were enrolled in the study (28 policosanol, 27 placebo). Twenty-three patients (17 placebo, 6 policosanol) required dose titration at 6 weeks. After 12 weeks of therapy, policosanol significantly decreased LDL-C with respect to baseline and placebo (both P < 0.001), showing a mean reduction of 32.6%. Total cholesterol (TC) and TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were reduced by 21.9%, 27.8%, and 37.2%, respectively, in the policosanol group (P < 0.001, compared with baseline and placebo). HDL-C rose 10.1% (P < 0.001), compared with baseline and placebo. Triglycerides were unaffected by policosanol. LDL-C, TC, and both atherogenic ratios were reduced significantly in the policosanol group (P < 0.001), and significant increases in HDL-C values were observed at the 6-week interim checkup (P < 0.001 vs baseline, P < 0.01 vs placebo). Twenty-five (89.3%) of 28 patients in the policosanol group showed LDL-C reductions >15% compared with 2 (7.4%) of 27 patients in the placebo group (P < 0.001). In addition, 26 (92.8%) of 28 policosanol patients reached LDL-C values < 3.4 mmol/L compared with 4 (14.8%) of 27 patients in the placebo group (P < 0.001). Likewise, the response rate for achievement of optimal values (LDL-C < 2.8 mmol/L) was also larger in the policosanol group (20/28; 71.4%) than in the placebo group (0/27; 0.0%) (P < 0.001). Policosanol was well tolerated, with no drug-related effects found on physical examination. Blood biochemistry determinations revealed significantly lower alanine aminotransferase levels in the policosanol group after 6 weeks of therapy compared with placebo (P < 0.05), as well as significant reductions in aspartate aminotransferase levels at 6 weeks (P < 0.01) and 12 weeks (P < 0.05) compared with baseline. No patients withdrew from the study, and only 3 patients (2 placebo, 1 policosanol) experienced mild AEs during the study; the placebo patients reported abdominal pain and constipation (1 each), and the policosanol patient reported polyphagia.Conclusions: Policosanol 5 mg/d appears to be well tolerated and effective as short-term treatment of hypercholesterolemia in adolescents.     

多廿醇对高脂血症大鼠血清胆固醇水平的影响

目的观察多廿醇对高脂血症大鼠的降胆固醇作用并探讨其作用机制。方法大鼠分为正常对照组、多廿醇4mg.kg-1预防组、高脂模型组、多廿醇4,6和8mg.kg-1治疗组和洛伐他汀阳性对照组;后5组大鼠在实验前4周给予高脂饲料制备高脂大鼠模型,从第5周开始,除正常对照和高脂模型组外,各给药组ig给予不同浓度的多廿醇或洛伐他汀,每天1次,连续6周。多廿醇预防组喂饲高脂饲料的同时ig多廿醇,每天1次,连续10周。用全自动生化分析仪测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平,并测定粪便总胆汁酸(FBA)排出量,紫外分光速率法测定肝脏微粒体3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶活性,荧光配体标记法测定外周血淋巴细胞低密度脂蛋白受体(LDL-R)活性。结果与高脂模型组比较,多廿醇预防组、多廿醇治疗组和洛伐他汀阳性对照组大鼠血清TC含量明显下降(39.1%～46.4%),LDL-C含量明显下降(66.6%～80.7%),粪便FBA明显升高(9.7%～19.0%),肝脏微粒体HMG-CoA还原酶活性明显下降(13.8%～23.6%),外周血淋巴细胞LDL-R活性升高(27.5%～129.6%);多廿醇预防组、多廿醇8mg.kg-1组和洛伐他汀组HDL-C水平明显升高(12.2%～16.7%);洛伐他汀组TG水平明显下降。结论多廿醇具有明显降低胆固醇的作用,其机制包括增加胆汁酸的排泄、抑制胆固醇合成限速酶HMG-CoA还原酶活性和促进低密度脂蛋白受体活性的表达。     

10 mg多廿烷醇与等剂量阿托伐他汀在血脂异常患者中调脂疗效比较的荟萃分析

目的 探讨比较10 mg多廿烷醇与等剂量阿托伐他汀在血脂异常患者中调脂的疗效。方法 检索维普网（VIP）、万方数据库、中国知网（CNKI）以及Cochrance图书馆、美国国立医学图书馆（PubMed）、科学引文索引数据库（Web of Science）、荷兰医学文摘（EMBASE）等数据库,查找10 mg多廿烷醇和10 mg阿托伐他汀的随机对照试验（RCT）和临床对照试验（CCT）,使用Cochrance Handbook 5.1.0评价系统或Newcastle-Ottawa量表（NOS）进行质量评价,采用RevMan5.2软件对纳入研究中的相关数据进行统计学分析。结果 共纳入4篇RCT文献,受试者257例,其中10 mg多廿烷醇组130例,10 mg阿托伐他汀组127例。荟萃（Meta）分析结果显示,在降低总胆固醇（TC）[SMD=0.84,95%CI：（0.41,1.27）,P=0.000 1]和低密度脂蛋白胆固醇（LDL-C）[SMD=0.68,95%CI：（0.28,1.09）,P=0.001]方面,10 mg阿托伐他汀组均优于10 mg多廿烷醇组;在升高高密度脂蛋白胆固醇（HDL-C）[SMD=0.27,95%CI：（0.02,0.51）,P=0.03]方面,10 mg多廿烷醇组优于10 mg阿托伐他汀组;在降低甘油三脂（TG）[SMD=0.10,95%CI：（-0.41,0.35）,P=0.42]方面,两组无统计学差异。结论 在血脂异常患者调脂治疗时,10 mg阿托伐他汀的疗效更优于等剂量的多廿烷醇,在替换阿托伐他汀治疗时应考虑增加多廿烷醇给药剂量,以保证调脂疗效。本研究存在纳入研究少、样本量小等局限性,结论的可靠性仍需多中心、大样本的高质量RCT研究加以验证。     

Effects of combination treatment with policosanol and omega-3 fatty acids on platelet aggregation: A randomized, double-blind clinical study

Background:

Policosanol is a mixture of long-chain primary aliphatic alcoholspurified from sugar cane wax that has cholesterol lowering and antiplatelet effects. Omega-3 fatty acids (FA) have triglyceride lowering and antiplatelet effects. Combination treatment with policosanol and omega-3 FA (Ω23FA) has been associated with significant inhibition of platelet aggregation in rabbits compared with either drug alone.

Objective:

The aim of this study was to investigate the effects of combination treatment with Ω3FA (1 g/d) and policosanol (Ω3FA+Poli) compared with Ω3FA (1 g/d) plus placebo (Ω3FA+Pla) on platelet aggregation in human patients with hypercholesterolemia.

Methods:

This randomized, double-blind, clinical study at the Surgical Medical Research Center (Havana City, Cuba) recruited outpatients from lipid clinics, with some atherosclerotic risk factors. Outpatients of both sexes aged 20 to 75 years with serum total cholesterol (TC) levels ≥5 and <6 mmol/L were eligible to enroll. They were included in the study at the end of a 4-week diet stabilization period if their platelet aggregation to arachidonic acid (AA) was ≥50% and serum TC level remained ≥5 mmol/L. Patients were then evenly randomized to receive Ω3FA (1 g/d) + placebo or Ω3FA (1 g/d) + policosanol (10 mg/d) to be taken PO with the evening meal for 21 days. Treatment was assigned according to a randomization code using balanced blocks and a 1:1 allocation ratio. Inhibition of platelet aggregation to AA was the primary efficacy variable, while effects on platelet aggregation to collagen and epinephrine and on lipid profile were secondary variables. Drug compliance and adverse events (AEs) were monitored. Tolerability was assessed using physical examinations and laboratory test results.

Results:

Sixty-four subjects were initially enrolled. Fifty-four patients (30 women, 24 men; mean [SD] age, 58.4 [12] years, [range, 40-70 years]) met the inclusion criteria and were randomized to treatment; 2 groups of 27. After 21 days, platelet aggregation to AA was significantly inhibited in the 2 groups. Ω3FA+Poli inhibited platelet aggregation to all agonists by ≥20%. Platelet aggregation to AA 1.0 and 1.5 mM was inhibited with combination treatment (39.6% and 33.9%, respectively; both P < 0.001 vs baseline; P < 0.001 and P < 0.01, respectively, vs Ω3FA+Pla) and with Ω3FA+Pla (11.0% and 13.3%; both, P < 0.001). Combination treatment was more effective in inhibiting platelet aggregation to AA 1.0 and 1.5 mM in 28.6% (P < 0.001) and 20.6% (P < 0.01), respectively. Platelet aggregation to collagen 1 μg/mL was significantly inhibited with combination treatment and with Ω3FA+Pla compared with baseline (43.2% and 15.1%, respectively; both, P < 0.001), but the effects of combination treatment were significantly greater (P < 0.01). Platelet aggregation to epinephrine 0.1 mM was inhibited with Ω3FA+Poli and Ω3FA+Pla (34.8% and 20.1%; both, P < 0.001), with similar results for both groups. Bleeding time did not change significantly for either group and Ω3FA+Pla did not significantly change the lipid profile. Combination treatment did significantly reduce levels of low-density lipoprotein cholesterol (LDL-C) (17.4%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla) and TC (10.1%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla), increase high-density lipoprotein cholesterol (HDL-C) levels (18.0%; P < 0.001 vs baseline), but did not significantly change triglyceride levels. Three patients (2 from the Ω3FA+Poli group and 1 from the Ω3FA+Pla group) withdrew from the trial, though none were due to AEs. Two patients receiving combination treatment reported mild AEs (headache). All treatments were well tolerated.

Conclusions:

In these patients, policosanol (10 mg/d) administered concomitantly with Ω3FA (1 g/d) enhanced the inhibition of platelet aggregation to AA and collagen, but not to epinephrine, compared with Ω3FA+Pla, without significantly affecting bleeding time. Concomitant treatment was also associated with reduced levels of LDL-C and TC and raised HDL-C levels. All treatments were well tolerated.     

多廿醇对人单核细胞低密度脂蛋白受体活性的影响

目的研究多廿醇对低密度脂蛋白受体(low density lipoprotein receptor,LDL-R)活性的影响,探讨多廿醇降脂作用的机制。方法体外试验采用常规细胞培养方法,观察多廿醇对人单个核细胞LDL-R的直接作用。体内试验采用自身和组间两种对照设计,观察多廿醇对高胆固醇血症人群LDL-R活性的影响。LDL-R活性检测选用荧光标记配体法。结果体外试验表明多廿醇在5～20mg·L-1范围内可以增强人单个核细胞LDL-R的活性,并且具有明显的量-效关系。体内试验中高胆固醇患者服用多廿醇20mg·d-14wk后,外周血单个核细胞LDL-R活性升高95%。结论多廿醇能通过增加LDL-R的活性而起降血脂作用,多廿醇降血脂是多途径的。     

Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro

AIMS: The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL-C to in vitro lipid peroxidation in human healthy volunteers. METHODS: The effect of policosanol (5 and 10 mg day(-1) on LDL-C oxidation was studied in a double-blind, randomized, placebo-controlled trial conducted in 69 subjects. LDL-C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL-C oxidation. We tested the susceptibility of LDL-C to lipid peroxidation in a cell-free system by the addition of copper ions as well as in a more physiological system, macrophage-mediated oxidation. RESULTS: At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose-dependent manner increased the lag phase of conjugated diene generation (mean +/- s.d.) from 83.79+/-29.16 min to 94.90+/-25.50 min (5 mg day(-1)) and from 82.74+/-17.16 min to 129.89+/-35.71 min (10 mg day(-1)), while in the placebo group LDL-C oxidation did not change significantly. Policosanol (10 mg day(-1)), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated-oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day(-1)) significantly lowered malondialdehyde (MDA) generation from 8.50+/-0.91 to 5.76+/- 1.01 nmol mg(-1) protein. Comparison with placebo after 5 and 10 mg day(-1) showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day(-1)) and 12.4% (10 mg day(-1)) and LDL-C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day(-1)) increased HDL-C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug-related disturbances were found. CONCLUSIONS: The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day(-1)), decreased the susceptibility of LDL-C to lipid peroxidation in vitro.