Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction.

AIMS: Recent secondary prevention trials have failed to demonstrate a beneficial effect of n-3 fatty acids on cardiovascular outcomes, which may be due to the growing use of statins since the mid-1990s. The aim of the present study was to assess whether statins modify the effects of n-3 fatty acids on major adverse cardiovascular events in patients with a history of myocardial infarction (MI). METHODS AND RESULTS: Patients who participated in the Alpha Omega Trial were divided into consistent statin users (n = 3740) and consistent statin non-users (n = 413). In these two groups of patients, the effects of an additional daily amount of 400 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), 2 g α-linolenic acid (ALA), or both on major cardiovascular events were evaluated. Multivariable Cox's proportional hazard models were used to calculate adjusted hazard rate ratios (HR(adj)). Among the statin users 495 (13%) and among the statin non-users 62 (15%) developed a major cardiovascular event. In statin users, an additional amount of n-3 fatty acids did not reduce cardiovascular events [HR(adj) 1.02; 95% confidence interval (CI): 0.80, 1.31; P = 0.88]. In statin non-users, however, only 9% of those who received EPA-DHA plus ALA experienced an event compared with 18% in the placebo group (HR(adj) 0.46; 95% CI: 0.21, 1.01; P= 0.051). CONCLUSION: In patients with a history of MI who are not treated with statins, low-dose supplementation with n-3 fatty acids may reduce major cardiovascular events. This study suggests that statin treatment modifies the effects of n-3 fatty acids on the incidence of major cardiovascular events.

Modelling approach to simulate reductions in LDL cholesterol levels after combined intake of statins and phytosterols/-stanols in humans.

BACKGROUND: To examine the effects on LDL cholesterol of the combined use of statins and phytosterols/-stanols, in vivo studies and clinical trials are necessary. However, for a better interpretation of the experimental data as well as to possibly predict cholesterol levels given a certain dosing regimen of statins and phytosterols/-stanols a more theoretically based approach is helpful. This study aims to construct a mathematical model to simulate reductions in low-density lipoprotein (LDL) cholesterol in persons who combine the use of statins with a high intake of phytosterols/-stanols, e.g. by the use of functional foods. METHODS AND RESULTS: The proposed model includes the cholesterol pool size in the liver and serum levels of very low-density lipoprotein (VLDL) cholesterol. Both an additional and a multiplicative effect of phytosterol/-stanol intake on LDL cholesterol reduction were predicted from the model. The additional effect relates to the decrease of dietary cholesterol uptake reduction, the multiplicative effect relates to the decrease in enterohepatic recycling efficiency, causing increased cholesterol elimination through bile. From the model, it was demonstrated that a daily intake of 2 g phytosterols/-stanols reduces LDL cholesterol level by about 8% to 9% on top of the reduction resulting from statin use. The additional decrease in LDL cholesterol caused by phytosterol/-stanol use at the recommended level of 2 g/d appeared to be similar or even greater than the decrease achieved by doubling the statin dose. CONCLUSION: We proposed a simplified mathematical model to simulate the reduction in LDL cholesterol after separate and combined intake of statins and functional foods acting on intestinal (re)absorption of cholesterol or bile acids in humans. In future work, this model can be extended to include more complex (regulatory) mechanisms.

Functional foods and dietary supplements: products at the interface between pharma and nutrition.

It is increasingly recognized that most chronic diseases of concern today are multifactorial in origin. To combat such diseases and adverse health conditions, a treatment approach where medicines and nutrition complement each other may prove to be the most successful. Within nutrition, apart from (disease-related) dietetic regimes, an increasing number of functional foods and dietary supplements, each with their own health claim, are marketed. These food items are considered to be positioned between traditional foods and medicines at the so-called 'Pharma-Nutrition Interface'. This paper encompasses aspects related to the regulatory framework and health claims of functional foods and dietary supplements. The use of functional foods or dietary supplements may offer opportunities to reduce health risk factors and risk of diseases, both as monotherapy and in combination with prescription drugs. Nevertheless, the potential caveats of these products should not be overlooked. These caveats include the increased risk for food-drug interactions due to the elevated amounts of specific functional ingredients in the diet, and the stimulation of self-medication potentially resulting in lower adherence to drug therapy. Health technology assessments should be used more to compare the cost-effectiveness and benefit-risk ratios of drugs, functional foods and dietary supplements, and to evaluate the added value of functional foods or dietary supplements to drug therapy.

Simultaneous intake of oat bran and atorvastatin reduces their efficacy to lower lipid levels and atherosclerosis in LDLr-/- mice.

The present study aimed to investigate the effects of separate and simultaneous dietary intake of atorvastatin (ATO) and the soluble fiber oat bran on serum and hepatic lipid levels and the degree of atherosclerosis. Ninety female LDL-receptor-deficient (LDLr-/-) mice were fed a Western-type diet containing either low dose (0.0025%), high dose (0.01%) or no ATO, with or without oat bran (27%) (n=15 per group) for 16 weeks. Both ATO and oat bran were effective in reducing serum total cholesterol levels (low ATO: -5.48, high ATO: -9.12, oat bran: -3.82 mmol/l, compared to control (no ATO/no oat bran), all p<0.0001). When oat bran was added to a low dose ATO, the cholesterol-lowering effects of this combination were 50% smaller compared to the low dose ATO diet alone (between-group difference: 2.77 mmol/l, p=0.002), whereas total cholesterol decreased to a similar extent in the groups fed a high dose ATO, with or without oat bran (between-group difference: 1.10 mmol/l, p=0.21). Serum LDL- and HDL-cholesterol, triglycerides, hepatic lipid levels and atherosclerotic lesion development showed a similar pattern. In conclusion, the efficacy of oat bran and atorvastatin to lower lipid levels and atherosclerosis is reduced after simultaneous intake. We hypothesize that oat bran inhibits the intestinal absorption of atorvastatin, and consequently its cholesterol-lowering effects. The effects are likely dependent on the type of statin and dietary fiber, and on the relative timing of intake of the statin and the dietary fiber. Future studies should focus on these aspects to provide further insight into the exact mechanism of this food-drug interaction.

Potato glycoalkaloids and adverse effects in humans: an ascending dose study.

Glycoalkaloids in potatoes may induce gastro-intestinal and systemic effects, by cell membrane disruption and acetylcholinesterase inhibition, respectively. The present single dose study was designed to evaluate the toxicity and pharmacokinetics of orally administered potato glycoalkaloids (alpha-chaconine and alpha-solanine). It is the first published human volunteer study were pharmacokinetic data were obtained for more than 24 h post-dose. Subjects (2-3 per treatment) received one of the following six treatments: (1-3) solutions with total glycoalkaloid (TGA) doses of 0.30, 0.50 or 0.70 mg/kg body weight (BW), or (4-6) mashed potatoes with TGA doses of 0.95, 1.10 or 1.25 mg/kg BW. The mashed potatoes had a TGA concentration of nearly 200 mg/kg fresh weight (the presently recognised upper limit of safety). None of these treatments induced acute systemic effects. One subject who received the highest dose of TGA (1.25 mg/kg BW) became nauseous and started vomiting about 4 h post-dose, possibly due to local glycoalkaloid toxicity (although the dosis is lower than generally reported in the literature to cause gastro-intestinal disturbances). Most relevant, the clearance of glycoalkaloids usually takes more than 24 h, which implicates that the toxicants may accumulate in case of daily consumption.

Applicability of an in vitro digestion model in assessing the bioaccessibility of mycotoxins from food.

Food is considered a major route of exposure to many contaminants. Only the fraction of the contaminant that is released from the food (bioaccessibility) and is bioavailable can exert toxic effects. Insufficient knowledge on the bioavailability may hamper an accurate risk assessment of ingested contaminants in humans. This paper describes the applicability of an in vitro digestion model allowing for measurement of the bioaccessibility of ingested mycotoxins from food as an indicator of oral bioavailability. Bioaccessibility of aflatoxin B(1) from peanut slurry and ochratoxin A from buckwheat was high, 94% and 100%, respectively, and could be determined reproducibly. With the in vitro digestion model, the bioaccessibilities of aflatoxin B(1) and ochratoxin A in the presence of four different absorption modulators were in five out of six situations in accordance with the in vivo effects in humans and animals. By determining the effect of chlorophyllin on the transport of aflatoxin B(1) across the intestinal Caco-2 cells, also the sixth combination was in agreement with data in humans. Hence, the in vitro digestion model, combined with Caco-2 cells, is a powerful experimental tool, which can aid to a more accurate risk assessment of ingested contaminants.