Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100

The in vivo pharmacokinetics/pharmacodynamics of 2′-O-(2-methoxyethyl) (2′-MOE) modified antisense oligonucleotides (ASOs), targeting apolipoprotein B-100 (apoB-100), were characterized in multiple species. The species-specific apoB antisense inhibitors demonstrated target apoB mRNA reduction in a drug concentration and time-dependent fashion in mice, monkeys, and humans. Consistent with the concentration-dependent decreases in liver apoB mRNA, reductions in serum apoB, and LDL-C, and total cholesterol were concurrently observed in animal models and humans. Additionally, the long duration of effect after cessation of dosing correlated well with the elimination half-life of 2′-MOE modified apoB ASOs studied in mice (t_1/2 ≅ 20 days) and humans (t_1/2 ≅ 30 days) following parental administrations. The plasma concentrations of ISIS 301012, observed in the terminal elimination phase of both mice and monkeys were in equilibrium with liver. The partition ratios between liver and plasma were similar, approximately 6000:1, across species, and thus provide a surrogate for tissue exposure in humans. Using an inhibitory E_max model, the ASO liver EC_50s were 101 ± 32, 119 ± 15, and 300 ± 191 μg/g of ASO in high-fat-fed (HF) mice, transgenic mice containing the human apoB transgene, and monkeys, respectively. The estimated liver EC₅₀ in man, extrapolated from trough plasma exposure, was 81 ± 122 μg/g. Therefore, extraordinary consistency of the exposure-response relationship for the apoB antisense inhibitor was observed across species, including human. The cross-species PK/PD relationships provide confidence in the use of pharmacology animal models to predict human dosing for second-generation ASOs targeting the liver.     

健康人性格类型与血清脂蛋白组分胆固醇相关性的研究

本文报告对1548名健康人性格类型与血清脂蛋白组分胆固醇的关系进行观察,结果表明A型性格者HDL-C、HDL_2-C、HDL_3-C、HDL_2-C/HDL_3-C均明显低于非A型性格者,而LDL-C/HDL-C则相反。性格类型对LDL-C和VLDL-C无明显影响。不同性别、年龄、职业人群观察结果相似。研究结果说明,A型性格易患冠心病的结论是可信的,性格类型影响血清脂蛋白组分胆固醇水平而发生致病作用可能是原因之一。     

Influence of chrysin on hepatic marker enzymes and lipid profile against d-galactosamine-induced hepatotoxicity rats

Chrysin is a flavonoid that exists in nature and is the major component of some traditional medicinal herbs. We investigated the hepatoprotective and antihyperlipidaemic potential of chrysin against d-galactosamine (a single intraperitoneal injection 400 mg/kg BW) induced hepatotoxicity in male albino Wistar rats. d-GalN rats exhibited an increased hepato and nephro toxicity marker activities aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase and total bilirubin level while urea, uric acid and creatinine and lipid profile. It also negatively affected the serum total protein, albumin and A/G ratio. Rats treated with chrysin at different concentrations (25, 50 and 100 mg/kg BW) caused a significant improvement in serum protein level, decreased hepato and nephro toxicity markers. It also decreased the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol while high density lipoprotein cholesterol significantly increased. It also decreased the levels of total cholesterol, phospholipids, triglycerides, free fatty acids in the plasma and tissues of liver and kidney. The effect of chrysin (25 mg/kg) is comparable with silymarin, a known hepatoprotective drug. Chrysin thus exhibits hepatoprotective and antihyperlipidaemic activity.     

In vitro effects of active components of Polygonum Multiflorum Radix on enzymes involved in the lipid metabolism

Ethnopharmacology relevance

Raw and processed Polygoni Multiflori Radix (PMR and PMRP) are used in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), hyperlipidemia or related diseases. In our previous research, 2, 3, 5, 4′-tetrahydroxy-stilbene-2-O-β-d-glucoside (TSG) displayed the most important role in the total cholesterol (TC) lowering effect among all the chemical constituents of Polygonum multiflorum. Emodin and physcion displayed more favorable triglyceride (TG) reducing effects than TSG. However, there are few researches focus on the approach and mechanism of how do Polygonum multiflorum exhibit good lipid regulation activity. The targeted sites of active substances of Polygonum multiflorum are still not clearly elucidated. This research pays close attention to how major chemical components of Polygonum multiflorum affect the TC and TG contents in liver cells.

Materials and methods

In this research, a sensitive, accurate and rapid in vitro model, steatosis hepatic L02 cell, was used to explore target sites of active chemical substances of Polygonum multiflorum for 48 h. Steatosis hepatic L02 cell was exposed to emodin, physcion and TSG, respectively. The contents of four key enzymes in the pathway of synthesis and decomposition of TC and TG were investigated after exposure. Meanwhile, the contents of lipid transfer protein were also tested. The diacylgycerol acyltransferase 1 (DGAT1) controlled the biosynthesis of TG from free fatty acids while 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) limited the biosynthesis of TC. Hepatic triglyceride lipase (HTGL) and cholesterol 7α-hydroxylase (CYP7A) played the key role in the lipolysis procedure of TG and TC.

Results

The synthesis of TC and TG in steatosis L02 cells were apparently increased in the model group compared to the control group. Intracellular contents of HMG-CoA reductase and DGAT1 increased 32.33% and 56.52%, while contents of CYP7A and HTGL decreased 21.61% and 47.37%. Emodin, physcion and TSG all showed down-regulation effects on HMG-CoA reductase, while up-regulation effects on CYP7A. The most remarkable effect on HMG-CoA reductase was found on emodin. Emodin could reduce the DGAT1 content from 438.44±4.51 pg/mL in model group to 192.55±9.85 pg/mL (100 μm). The content of HTGL in 300 μm physcion group was 3.15±0.15 U/mL, which was more significantly effective than the control, lovastatin and fenofibrate group.

Conclusions

TSG could raise the content of CYP7A and then promote the lipolysis of cholesterol. Moreover, TSG also showed the best LDL-reducing effect. Emodin could inhibit HMG-CoA reductase and DGAT1, which were key enzymes in the synthesis of TC and TG. Physcion increased the content of HTGL, and then could boost the lipolysis of triglyceride. At the same time, physcion showed the best VLDL-reducing effect. In view of the above conclusions, we contributed the lipid regulation activity to an overall synergy of TSG, emodin and physcion.     

Antihyperglycemic,hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis in experimental type 2 diabetic rats

Ethnopharmacological relevance

As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has multiple pharmacological activities, including relieving rheumatism, promoting blood circulation to arrest pain, inducing diuresis to reduce edema, and antidiabetic action. It has long been used as a folk medicine for the treatment of traumatic injury, rheumatic arthralgia, nephritis, edema, hepatitis and diabetes mellitus in China.

Aim of study

To evaluate the antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis (SAT) in experimental type 2 diabetic mellitus (T2DM) rats.

Materials and methods

Acute toxicity was studied in rats to determine the safe oral dose of SAT. Then, SAT was given orally to normal and streptozotocin–nicotinamide induced T2DM rats at 80, 160 and 320 mg/kg doses for a series of 28 days to determine the antihyperglycemic activity. Glibenclamide (600 μg/kg), a standard antidiabetic drug, was used as a positive control drug. At the end of treatment, biochemical parameters and antioxidant levels were measured to evaluate the hypolipidemic and antioxidant activities of SAT.

Results

Oral administration of SAT did not exhibit toxicity and death at a dose not more than 2000 mg/kg. SAT dose-dependently improved the symptoms of polydipsia, polyuria, polyphagia and weight loss in diabetic rats. Compared with diabetic control group, administration of 320 mg/kg SAT resulted in significant (P<0.05) fall in the levels of fasting blood glucose, glycosylated hemoglobin, creatinine, urea, alanine transarninase, aspartate aminotransferase, total cholesterol, triglycerides, low density lipoprotein cholesterol and malondialdehyde, but significant (P<0.05) increase in the levels of serum insulin, superoxide dismutase and reduced glutathione. However, SAT did not have any effect on the normal rats.

Conclusions

SAT had excellent antihyperglycemic, hypolipidemic and antioxidant activities in T2DM rats and might be a promising drug in the therapy of diabetes mellitus and its complications.     

吸烟对健康人血清HDL-C等7项指标水平影响的对比观察

经对生活和工作环境相似的40~69岁健康男性工人吸烟组697人和不吸烟组841人的对比观察,说明吸烟对健康人血清脂蛋白组分胆固醇水平有明显影响。吸烟组HDL-C、HDL₂-C、HDL₃-C、HDL₂-C/HDL₃-C明显低于不吸烟组,LDL-C、VLDL-C、LDL-C/HDL-C明显高于不吸烟组,且与吸烟量、时间、习惯呈剂量反应关系。吸烟是降低HDL-C、HDL₂-C、HDL₃-C、HDL₂-C/HDL₃-C和升高LDL-C、VLDL-C、LDL-C/HDL-C的危险因素。与不吸烟组相比,吸烟降低HDL-C等4项指标水平和升高LDL-C等3项指标水平的RR分别为1.09~5.77和2.37~3.59。被动吸烟者HDL-C等7项指标水平与轻度吸烟者相似,说明被动吸烟对血清脂蛋白组分胆固醇有明显影响。     

Hypertriglyceridemia: A Review of Clinical Relevance and Treatment Options: Focus on Cerivastatin

SUMMARY

The triglyceride (TG) level is one of several lipid parameters that can aid prediction of coronary heart disease (CHD) risk. An elevated plasma TG level is strongly associated with an increased risk of CHD.

Hypertriglyceridemia, the second most common dyslipidemic abnormality in hypertensive subjects after increased low-density lipoprotein cholesterol (LDL-C), is defined by the National Cholesterol Education Programme (NCEP) as a fasting TG level of >2.26?mmol/l (>200?mg/dl) and is recognised as a primary indicator for treatment in type IIb dyslipidemia. Raised TG levels can be present in individuals at risk for CHD when the total cholesterol is normal. However, not all individuals with raised TG levels have increased risk of CHD. Factors such as: diet, age, lifestyle, and a range of medical conditions, drug therapy and metabolic disorders, can all affect the TG level. In some of these circumstances, other factors protect against the risk of CHD, and can minimise or negate the effect of the risk factors present.

Although TG reducing therapy has been shown to be associated with an improved clinical outcome, more research is needed to determine whether this is an independent effect of TG reduction or an effect of normalising the overall lipid profile in hypertriglyceridemic patients. Further trials are required to quantify the clinical benefits of lowering TG to ‘target’ levels and to confirm targets defined by NCEP-II (shown in Table 1).

The role of TG in CHD pathogenesis is thought to involve several direct and indirect mechanisms, such as effects on the metabolism of other lipoproteins, transport proteins, enzymes, and on coagulation and endothelial dysfunction. More research is required to fully elucidate the role of TG, the ways in which it can influence other risk factors and the mechanism of its own more direct role in the atherogenic process.

Patients with hypertriglyceridemia have been shown to respond well to dietary control and to the use of lipid lowering drugs such as 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors (known as statins), fibrates and nicotinic acids. However, recent retrospective real-life clinical studies show that only 38% of patients receiving some form of lipid-lowering therapy achieved NCEP-defined LDL-C target levels, demonstrating the need for the use of more aggressive treatment.

In hypertriglyceridemic patients, the newer statins, cerivastatin and atorvastatin, have shown comparable efficacy in reducing TG compared with the older statins. Achieving NCEP target lipid levels has been shown to reduce the risk of cardiovascular disease in dyslipidemic individuals, including high-risk patient groups such as those with additional risk factors, existing heart disease, diabetes mellitus and metabolic syndrome.

Although the latest clinical studies investigating combination therapies, i.e. dual therapy with both a statin and a fibrate, have demonstrated them to be effective for overall control of lipid parameters and reducing coronary events, it is not yet clear whether this offers any significant advantage over monotherapy. Results from ongoing longer-term end-point clinical studies may provide further information in this area and consequent reviews of primary care management policies for dyslipidemia. Statin monotherapy may be a reliable option for primary care treatment of dyslipidemia (including hypertriglyceridemia).     

Antihyperglycemic and antihyperlipidemic activities of methanol:water (4:1) fraction isolated from aqueous extract of Syzygium alternifolium seeds in streptozotocin induced diabetic rats

The present study was taken up to identify potent antihyperglycemic fraction from the aqueous extract of Syzygium alternifolium (SA) seeds, using bioassay guided fractionation. The isolated fraction C at a dose of 50 mg/kg.b.w produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 6 h of the treatment. The administration of fraction C (50 mg/kg.b.w) once daily for 30 days in STZ diabetic rats resulted in a significant decrease in blood glucose, glycosylated haemoglobin with a significant rise in plasma insulin level. Further fraction C showed antihyperlipidemic activity as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic rats. A significant decrease in the activities of SGOT, SGPT, ALP and decreased levels of serum urea and creatinine in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage and non-toxic property of the fraction C. A comparison was made between the action of fraction C and antidiabetic drug glibenclamide (20 mg/kg.b.w). The effect of fraction C was more prominent when compared to that of glibenclamide.     

Exercise attenuates the increase in plasma monounsaturated fatty acids and high-density lipoprotein cholesterol but not high-density lipoprotein 2b cholesterol caused by high-oleic ground beef in women

We hypothesized that dietary monounsaturated fatty acids (MUFA) and exercise increase high-density lipoprotein cholesterol (HDL-C) by independent mechanisms, so there would be additive effects between a single, intensive session of exercise and high-MUFA ground beef on HDL-C and blood risk factors for cardiovascular disease. Seventeen postmenopausal women completed a 2-way crossover design in which they consumed five 114-g ground beef patties per week for two 6-week periods separated by a 4-week washout (habitual diet) period. The ground beef patties contained 21% total fat with either 9.97 (low-MUFA) or 12.72 (high-MUFA) g total MUFA. Blood was taken at entry, at the end of each 6-week diet period, after the 4-week washout period, and 24 hours after aerobic exercise sessions (75% VO_2peak, 2.07 MJ). After the ground beef intervention, the high-MUFA ground beef increased plasma palmitoleic acid and oleic acid, low-density lipoprotein (LDL) particle density, HDL-C, and HDL_2b-C (all P < .05), whereas the low-MUFA ground beef increased LDL density. After the washout (habitual diet) period, the single exercise session increased serum LDL cholesterol, HDL-C, and HDL_2a and decreased TAG and oleic acid. After the low-MUFA ground beef diet, exercise increased LDL size and HDL density and decreased LDL density and very low-density lipoprotein cholesterol, but had no effect on HDL-C fractions. After the high-MUFA ground beef intervention, exercise decreased palmitioleic acid, oleic acid, HDL-C, and HDL_2a-C, but not HDL_2b-C. Contrary to our hypothesis, the effects of exercise and a high-MUFA diet were not additive; instead, exercise attenuated the effects of the high-MUFA ground beef on HDL-C and plasma MUFAs. The differential effects of high-MUFA ground beef and exercise on HDL_2a-C and HDL_2b-C indicate that diet and exercise affect HDL-C by different mechanisms.     

健康小儿红细胞内外脂蛋白组分胆固醇水平及影响因素的研究

研究健康小儿红细胞内外脂蛋白组分胆固醇水平及影响因素,以便为幼龄开始的心血管病防治提供依据。观察新生儿、2岁～、7岁～、12～15岁4个年龄组健康小儿808名,研究性别、年龄、运动、体质指数、遗传对 RBC-C、HDL-C、HDL_2-C、HDL_3-C、LDL-C、VLDL-C、LDL-C/HDL-C、HDL_2-C/HDL_3-C_8项指标水平的影响。结果表明,性别、年龄,遗传对红细胞内外脂蛋白组分胆固醇有较明显的影响,而体质指数,运动的影响不明显。