Archive for September, 2011

omega-3 fish oil , weight status and insulin resistance in children.

Tuesday, September 13th, 2011

Int J Pediatr Obes. 2011 Jun;6(2-2):e532-9. Epub 2011 Jan 12.
Omega-3 index, obesity and insulin resistance in children.

Burrows T, Collins CE, Garg ML.
Source

School of Health Sciences, University of Newcastle , Callaghan, NSW, Australia. Tracy.burrows@newcastle.edu.au

Abstract

OBJECTIVES:

Recent studies in adults have suggested that the plasma level of omega-3 fatty acids may be associated with weight status and abdominal adiposity, limited studies exist in paediatric populations. The present study examined the relationship between the omega-3 index, weight status and insulin resistance in children.

METHODS:

School-age children between 5-12 years, classified as non-obese or obese on the basis of body mass index (BMI) z-scores, were examined. Fat intake was assessed using a parent reported 135-item semi-quantitative food frequency questionnaire. Erythrocyte fatty acid composition was determined using gas chromatography. The Omega-3 index (O3I) was calculated by adding eicosapentaenoic and docosahexaenoic acid % (weight/weight) values.

RESULTS:

Obese children had altered erythrocyte fatty acid composition unrelated to reported dietary intake. A greater proportion of obese (BMI z-score > 2.25) children (33%) had an omega-3 index of < 4.0 (high risk) compared with non-obese children (BMI z-score < 2.25) (17%). Simultaneously, the number of children with a higher omega-3 index (6.0-8.0 lower risk) was lower in the obese (13%) versus non-obese children (25%, respectively). A moderate, but statistically significant correlation was found between O3I and fasting insulin level (r = -0.3, P = 0.03) and with homeostatic model assessment (HOMA) scores (r = -0.3, P = 0.04). CONCLUSION; The observed association between the omega-3 index, weight status and insulin resistance in children highlights the importance of omega-3 fatty acids in the prevention of obesity-related chronic diseases in later life. The results presented merits confirmation in a larger sample of obese children.

Omega-3 fatty acid supplementation in cancer therapy : does omega 3 EPA ( eicosapentanoic acid) influence the radiosensitivity of tumor cells?

Tuesday, September 13th, 2011

Omega-3 fatty acid supplementation in cancer therapy : does eicosapentanoic acid influence the radiosensitivity of tumor cells?

Manda K, Kriesen S, Hildebrandt G, Fietkau R, Klautke G.
Source

Department of Radiotherapy, University of Rostock, Rostock, Germany. katrin.manda@uni-rostock.de

Abstract

PURPOSE:

The aim of this study was to evaluate whether the omega-3 polyunsaturated fatty acid cis-5,8,11,14,17-eicosapentanoic acid (EPA) can enhance the radiosensitivity of different human tumor cell lines.

MATERIALS AND METHODS:

Colon adenocarcinoma cells HT-29, and two glioblastoma multiforme tumor cells T98G and U251 were cultured under standard conditions. Cell growth was observed during administration with different concentrations of EPA, using it as the free fatty acid dissolved in ethanol or bound to bovine serum albumin. To investigate the influence of EPA (free and bound) on radiosensitivity, tumor cells were pretreated 30 minutes or 24 hours prior to irradiation with the fatty acid. Cell survival was measured by colony-forming assays.

RESULTS:

When combined with irradiation, incubation with EPA was found to result in enhanced radiosensitivity with substantial variation: while there was strong radiosensitization for HT-29 and U251 cells, almost no effect for T98G cells was observed. A marked radiosensitization was clearly dependent on the treatment schedule.

CONCLUSION:

The observations suggest that EPA is not only a nutritional adjuvant but also may be a potential candidate to enhance the efficacy of irradiation on human cancer cells.

Omega 3 EPA and DHA Fish oil supplementation alters levels of lipid mediators of inflammation in microenvironment of acute human wounds.

Tuesday, September 13th, 2011

Omega 3 Fish oil supplementation alters levels of lipid mediators of inflammation in microenvironment of acute human wounds.

McDaniel JC, Massey K, Nicolaou A.
Source

College of Nursing, The Ohio State University, Columbus, Ohio 43210-1289, USA. mcdaniel.561@osu.edu

Abstract

Chronic wounds often result from prolonged inflammation involving excessive polymorphonuclear leukocyte activity. Studies show that the ω-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oils generate bioactive lipid mediators that reduce inflammation and polymorphonuclear leukocyte recruitment in numerous inflammatory disease models. This study’s purpose was to test the hypotheses that boosting plasma levels of EPA and DHA with oral supplementation would alter lipid mediator levels in acute wound microenvironments and reduce polymorphonuclear leukocyte levels. Eighteen individuals were randomized to 28 days of either EPA+DHA supplementation (Active Group) or placebo. After 28 days, the Active Group had significantly higher plasma levels of EPA (p<0.001) and DHA (p<0.001) than the Placebo Group and significantly lower wound fluid levels of two 15-lipoxygenase products of ω-6 polyunsaturated fatty acids (9-hydroxyoctadecadienoic acid [p=0.033] and 15-hydroxyeicosatrienoic acid [p=0.006]), at 24 hours postwounding. The Active Group also had lower mean levels of myeloperoxidase, a leukocyte marker, at 12 hours and significantly more reepithelialization on Day 5 postwounding. We suggest that lipid mediator profiles can be manipulated by altering polyunsaturated fatty acid intake to create a wound microenvironment more

Omega-3 high EPA formulation Effective for Treating Child ADHD

Sunday, September 11th, 2011

September 8, 2011 — Supplementation with omega-3 fatty acid may decrease symptoms of attention-deficit/hyperactivity disorder (ADHD) in children, a new meta-analysis suggests.

In an evaluation of 10 trials with 699 total children with ADHD, investigators found that those who received omega-3 supplements had a “small but significant” improvement in symptom severity compared with those who were given placebo. This effect was also significant in the children who received supplements that specifically contained higher doses of eicosapentaenoic acid.

“I was actually expecting this treatment to not be effective at all, that we shouldn’t expect much from a nutritional supplement that often takes a while to work. So the results were a surprise to me,” lead author Michael H. Bloch, MD, assistant professor at the Yale Child Study Center at Yale University School of Medicine in New Haven, Connecticut, told Medscape Medical News.

omega-3 represents a potentially safer alternative, especially in mild cases,” said Dr. Bloch.

The study was published online August 16 in the Journal of the Academy of Child and Adolescent Psychiatry.

Past Research Results “Mixed”

According to the investigators, past research has shown that individuals with ADHD have omega-3 differences in both plasma and erythrocyte membranes compared with their healthy peers.

“Omega-3 fatty acids have anti-inflammatory properties and can alter central nervous system cell membrane fluidity and phospholipid composition,” they explain.
Omega-3 supplements that included higher doses of eicosapentaenoic acid were also significantly associated with lowering ADHD symptoms (P = .04).

There were no significant differences found for any dose of docosahexaenoic acid or α-linolenic acid,
However, “because of poor quality and potential issues of blinding in many of the included trials,” further studies are needed to replicate the results, they write.

“I think this is something that’s potentially useful for families who either don’t respond to treatment with traditional medications or are hesitant to take them because of side effects,” said Dr. Bloch.

He added that he hopes a future multisite trial with at least 400 children will be conducted to finally give “a definitive answer on how much omega-3 might really work.”

Predictors of omega-3 index in patients with acute myocardial infarction

Saturday, September 10th, 2011

Source

Department of Cardiovascular Diseases, Saint Luke’s Mid-America Heart and Vascular Institute, Kansas City, MO 64111, USA. salisbury.adam@yahoo.com

Abstract

OBJECTIVE:

To identify the patient and dietary characteristics associated with low omega-3 levels in patients with acute myocardial infarction (AMI) and determine whether these characteristics are useful to identify patients who may benefit from omega-3 testing and treatment.

PATIENTS AND METHODS:

Dietary habits of 1487 patients in the 24-center Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status (TRIUMPH) registry between April 11, 2005, and September 28, 2007, were assessed by asking about the frequency of fast food and nonfried fish consumption. All patients had erythrocyte omega-3 index measured at the time of hospital admission for AMI. We used multivariable linear regression to identify independent correlates of the omega-3 index and modified Poisson regression to predict risk of a low omega-3 index (<4%).

RESULTS:

The proportion of patients with a low omega-3 index increased with more frequent fast food intake (18.9% for <1 time monthly, 28.6% for 1-3 times monthly, 28.8% for 1-2 times weekly, and 37.6% for ≥ 3 times weekly; P<.001). In contrast, a low omega-3 index was less common among patients with more frequent fish intake (35.1% for <1 time monthly, 24.9% for 1-3 times monthly, 16.1% for 1-2 times weekly, and 21.1% for ≥ 3 times weekly; P<.001). Fish intake, older age, race other than white, and omega-3 supplementation were independently associated with a higher omega-3 index, whereas frequent fast food intake, smoking, and diabetes mellitus were associated with a lower omega-3 index.

CONCLUSION:

Potentially modifiable factors, such as patient-reported fast food intake, fish intake, and smoking, are independently associated with the omega-3 index in patients with AMI. These characteristics may be useful to identify patients who would benefit most from omega-3 supplementation and lifestyle modification.Salisbury ACAmin APHarris WSChan PSGosch KLRich MWO’Keefe JH JrSpertus JA.

Source

Department of Cardiovascular Diseases, Saint Luke’s Mid-America Heart and Vascular Institute, Kansas City, MO 64111, USA. salisbury.adam@yahoo.com

Abstract

OBJECTIVE:

To identify the patient and dietary characteristics associated with low omega-3 levels in patients with acute myocardial infarction (AMI) and determine whether these characteristics are useful to identify patients who may benefit from omega-3 testing and treatment.

PATIENTS AND METHODS:

Dietary habits of 1487 patients in the 24-center Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status (TRIUMPH) registry between April 11, 2005, and September 28, 2007, were assessed by asking about the frequency of fast food and nonfried fish consumption. All patients had erythrocyte omega-3 index measured at the time of hospital admission for AMI. We used multivariable linear regression to identify independent correlates of the omega-3 index and modified Poisson regression to predict risk of a low omega-3 index (<4%).

RESULTS:

The proportion of patients with a low omega-3 index increased with more frequent fast food intake (18.9% for <1 time monthly, 28.6% for 1-3 times monthly, 28.8% for 1-2 times weekly, and 37.6% for ≥ 3 times weekly; P<.001). In contrast, a low omega-3 index was less common among patients with more frequent fish intake (35.1% for <1 time monthly, 24.9% for 1-3 times monthly, 16.1% for 1-2 times weekly, and 21.1% for ≥ 3 times weekly; P<.001). Fish intake, older age, race other than white, and omega-3 supplementation were independently associated with a higher omega-3 index, whereas frequent fast food intake, smoking, and diabetes mellitus were associated with a lower omega-3 index.

CONCLUSION:

Potentially modifiable factors, such as patient-reported fast food intake, fish intake, and smoking, are independently associated with the omega-3 index in patients with AMI. These characteristics may be useful to identify patients who would benefit most from omega-3 supplementation and lifestyle modification.

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPAR α/γ activity in microvascular endothelial cells.

Saturday, September 10th, 2011

Raffaele De Caterina, MD, PhD, Institute of Cardiology, “G. d’Annunzio” University – Chieti, C/o Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy, Tel: +39 0871 41512, Fax: +39 0871 553 461, E-mail: rdecater@unich.it.

Abstract

Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10⁻⁸ and 10⁻⁷ M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ℜ∓ 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.

Effect of dietary fish oil on atrial fibrillation after cardiac surgery.

Saturday, September 10th, 2011

Effect of dietary fish oil on atrial fibrillation after cardiac surgery.

Source

Discipline of Medicine, University of Adelaide, Adelaide, Australia.

Abstract

An open-label study reported that ingestion of a fish oil concentrate decreased the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery. However, a general cardiac surgery population involves valve and CABG surgeries. We undertook a double-blinded randomized controlled trial to examine the effectiveness of fish oil supplementation on the incidence of postsurgical AF after CABG and valve procedures. The primary end point was incidence of AF in the first 6 days after surgery. Two hundred patients were randomized to receive fish oil (providing 4.6 g/day of long-chain ω-3 fatty acids) or a control oil starting 3 weeks before surgery; 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing AF (odds ratio 0.63, 95% confidence interval [CI] 0.35 to 1.11). There was a nonstatistically significant delay in time to onset of AF in the fish oil group (hazard ratio 0.66, 95% CI 0.43 to 1.01). There was a significant decrease in mean length of stay in the intensive care unit in the fish oil group (ratio of means 0.71, 95% CI 0.56 to 0.90). In conclusion, in a mixed cardiac surgery population, supplementation with dietary fish oil did not result in a significant decrease in the incidence of postsurgical AF. However, there was a significant decrease in time spent in the intensive care unit.

Clinical:Treatment of HIV-Associated Dyslipidemia: A Role for Omega-3 Fatty Acids

Saturday, September 10th, 2011

Highly active antiretroviral therapy and the adverse metabolic effects of HIV infection itself are associated with the development of cardiovascular risk factors. By itself, HIV infection is associated with atherogenic dyslipidemia, which includes low levels of high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia.[1][2] Antiretroviral therapy may exacerbate lipid abnormalities, and dyslipidemia may develop in up to 70% to 80% of treated HIV-infected patients, with hypertriglyceridemia occurring in the majority of cases (60% to 100% of treated patients).[3] The presence of hypertriglyceridemia enhances the development of small, dense low-density lipoprotein (LDL) particles, a recognized atherogenic phenomenon that may be accentuated by regimens that contain lopinavir/ritonavir, for example.[4] Protease inhibitor (PI) therapy may also depress HDL-C levels, although other classes of antiretroviral agents may have a more neutral or favorable effect on this parameter.

The National Cholesterol Education Program (NCEP) Adult Treatment Program III (ATP III) has made recommendations for treatment of dyslipidemia in HIV-infected patients.[5] While acknowledging that there is limited experience with lipid-modifying drugs in this population and minimal documentation that such therapies will prevent cardiovascular disease (CVD) in patients with HIV-associated dyslipidemia, the guidelines recognize that drug treatment can help control the lipid abnormalities that may occur.

Management of triglyceride levels may be especially important because of the risk of pancreatitis associated with extreme triglyceride level elevations. As in uninfected patients, lipid risk-factor management should focus on lowering LDL cholesterol (LDL-C) levels, and drug options include statins. For other aspects of HIV-associated dyslipidemia, fibrates,[6] nicotinic acid,[7] and omega-3 fatty acids[8][9][10] alone or in combination may help lower triglyceride levels. This article examines the evolving knowledge of the management of antiretroviral-related and HIV-related dyslipidemia, with a focus on reducing triglyceride levels with omega-3 fatty acids.

HIV, ANTIRETROVIRAL THERAPY, DYSLIPIDEMIA, AND CARDIOVASCULAR RISK

Potential Mechanisms of HIV-Associated Dyslipidemia

HIV infection itself is associated with dyslipidemia. Indeed, changes in lipid levels and, to a lesser extent, glucose metabolism were found in persons with HIV infection before the advent of effective antiretroviral therapy.[11] In 1991, Grunfeld and colleagues[12] showed a highly significant correlation between circulating interferon-a levels and serum triglyceride levels in HIV-infected patients. Other causative factors may include an increase in the cortisol-to-dehydroepiandrosterone ratio.[13]

Hypertriglyceridemia is also associated with antiretroviral therapy. In a study of 113 HIV-infected patients treated with PIs compared with 45 HIV-infected nonusers, Carr and colleagues[14] reported a higher baseline prevalence of triglyceride levels greater than 2.0 mmol/L (177 mg/dL) (50% vs 22%, respectively), total cholesterol levels greater than 5.5 mmol/L (213 mg/dL) (58% vs 11%, respectively), and combined hypertriglyceridemia/hypercholesterolemia (38% vs 5%, respectively) in PI users than in nonusers.

Segerer and colleagues[15] reported a 15% increase in total cholesterol levels and a 25% increase in triglyceride levels from baseline after 3 to 6 months in patients using saquinavir, ritonavir, nelfinavir, or indinavir. PIs are associated with dyslipidemia either directly (through induction of cholesterol or fatty-acid biosynthesis) or indirectly (through the development of insulin resistance). Potential mechanisms include altered adipogenesis and lipolysis and increased synthesis of hepatic triglycerides.[16][17][18][19] Moreover, dyslipidemia has been observed in patients treated with the nucleoside analogue stavudine[20][21][22] and the NNRTI efavirenz.[23]

The term “HIV lipodystrophy syndrome” describes the constellation of clinical findings, including peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance.[24] Although the causes of visceral fat hypertrophy are not yet known, PIs and NRTIs have been shown to decrease differentiation and adipogenesis in subcutaneous adipose tissue.[25] The reader is referred to a recent review for a detailed discussion of the potential mechanisms for metabolic abnormalities in HIV-infected patients receiving antiretroviral therapy.[26]

Prevalence of Cardiovascular Disease

Improved therapeutic management of HIV disease has reduced mortality due to opportunistic infections or other sequelae of HIV infection. As a consequence of this improvement, however, HIV-infected patients now may be vulnerable to other causes of morbidity and mortality.[27][28][29] Before the HAART era, reports of CVD in association with HIV were infrequent, perhaps because the patients did not live long enough for CVD to develop. CVD can be associated with HIV infection, opportunistic infections or neoplasias, mode of HIV acquisition (such as injection drug use), antiretroviral therapy, or the classic non–DHIV-related cardiovascular risk factors (such as smoking or older age).[30] Dyslipidemia and vascular inflammation are considered the 2 main sources of CVD in patients with HIV disease.[31]

The long-term use of PI therapy has been associated with an increased risk of myocardial infarction (MI) and coronary disease. The Kaiser Permanente Registry study reviewed data from the Kaiser Permanente HMO.[32] The 2004 tally identified 4726 HIV-positive patients aged 35 to 64 years from January 1996 through June 2003. These patients had an age-adjusted coronary heart disease (CHD) rate of 6.6 (vs 3.0 in those without HIV) per 1000 patient-years (P < .0001). The ageadjusted rate of MI in patients receiving PIs was 3.9 (vs 2.2 in those not receiving PIs) per 1000 patient-years (P < .005). The median time of PI exposure was 4.0 years.

Omega-3 fatty acids are polyunsaturated fatty acids in which the first double bond from the terminal (omega) methyl group is at carbon 3.[55] Omega-3 (α-linolenic acid, eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) fatty acids are 1 of the 2 classes of essential fatty acids. Only small amounts of plant-derived omega-3 fatty acids are converted to EPA in vivo, and further transformation to DHA is very low. In the United States, the average intake of omega-3 fatty acids is about 100 to 200 mg/d.[56]

A combined daily dose of 3.4 g of EPA and DHA is required to achieve the reduction needed in patients with very high triglyceride levels.[57][58] Fatty fish, such as albacore tuna, sardines, salmon, mackerel, and herring, are the most concentrated food source of EPA and DHA.[59][60] However, consumption of fatty fish is not likely to provide sufficient amounts of DHA and EPA for the effective management of hypertriglyceridemia. For example, a person would need to consume 16 oz of canned albacore tuna per day to obtain approximately 4 g of EPA and DHA.[61] Moreover, some larger species of fish (eg, shark, king mackerel, swordfish, and tilefish) contain high levels of methylmercury, dioxins, and polychlorinated biphenyls.[62][63]

In the United States, dietary supplements with the omega-3 fatty acids EPA and DHA are available over the counter as well as in a prescription formulation. The prescription formulation is indicated as an adjunct to diet to reduce very high triglyceride levels (500 mg/dL or higher) in adults. For triglyceride reduction, this agent can be taken either as a single 4-g dose (4 capsules) or as two 2-g doses (2 capsules twice daily).[64]

Mechanism of action. After oral administration of omega-3 fatty acids in both healthy volunteers and patients with hypertriglyceridemia, EPA and DHA are well absorbed and lead to significant, dose-dependent increases in serum phospholipid EPA content.[65] Although details on the cellular mechanisms by which omega-3 fatty acids reduce serum triglyceride levels are not completely understood, EPA and DHA may reduce very-low-density lipoprotein (VLDL)-triglyceride synthesis,[66] enhance triglyceride clearance from VLDL particles,[67] and/or increase conversion of VLDL remnants to LDL.[68] The reader is referred to a recent review for a detailed discussion of potential mechanisms for the triglyceride-lowering effects of omega-3 fatty acids.[69]

Efficacy and safety in the general population. Potential cardioprotective effects of omega-3 fatty acids were first recognized when indigenous populations who consumed high concentrations of EPA and DHA—such as marine mammals and fatty fish––were observed to have low rates of CHD. In patients with established CHD, omega-3 fatty-acid intake is associated with a reduced risk of mortality from MI and sudden death.[70]

Omega-3 fatty acids have been shown to lower serum triglyceride levels in a dose-dependent manner in both crossover and parallel-design studies of participants with mean baseline triglyceride levels less than 2 mmol/L or those with levels 2 mmol/L and higher.[71] EPA and DHA, which appear to have similar triglyceride-lowering effects,[72] can reduce triglyceride levels in a wide range of patient types.[73][74] Clinical studies have shown that EPA and DHA lower fasting[75] and postprandial64. [76][77][78][79][80] triglyceride levels without clinically significant effects on fat absorption.

A review of 10 randomized, controlled trials of participants with triglyceride levels greater than 150 mg/dL (greater than 1.[81] mmol/L) showed that among patients taking EPA and/or DHA in dosages of 3.4 to 4 g/d, triglyceride levels were reduced by an average of 29% (range, 16% to 45%).[82] Treatment with omega-3 fatty acids may induce modest increases in HDL-C levels on the order of 10% but also may raise LDL-C levels to varying degrees. The safety and efficacy of omega-3 fatty acids for the treatment of hypertriglyceridemia in the general population is well documented.[83][84][85][86][87][88][89][90]

As reported to the FDA, pooled data from 8 randomized, placebo-controlled, double-blind, parallel-group studies conducted in participants with hypertriglyceridemia have shown that treatment with omega-3 fatty acids is safe and well tolerated.[91] In clinical trials, the most common adverse events were eructation, infection, dyspepsia, and flu syndrome.[92] The only adverse event occurring significantly more frequently with omega-3 fatty acids than with placebo was “taste perversion” (principally, “fishy taste”) at an incidence of 2.7% with omega-3 fatty acids vs 0% with placebo (P = .0147). Adverse events led to treatment discontinuation in 3.5% of patients treated with omega-3 fatty acids, compared with 2.6% of patients who received placebo.[93]

Because free forms of EPA and DHA are not detected in the circulation, drug interactions due to the inhibition of cytochrome P-450 are not expected.[94] The antithrombotic effects of omega-3 fatty acids have raised concerns about prolonged bleeding time, but clinical trials have not shown an increased risk of bleeding.[95] Although omega-3 fatty acids have been shown to reduce thrombin generation in a vitamin K–independent manner,[96] to date, there are no published data showing significant changes in bleeding time or propensity for bleeding among patients treated with FDA-approved doses of omega-3 fatty acids.

No experience with concurrent clopidogrel therapy has been reported; however, experience with omega-3 fatty acid therapy in patients receiving coumarin anticoagulants, aspirin, and other older antiplatelet agents has not revealed increased bleeding. A study of the interaction between fish oil and warfarin did not show increases in international normalized ratios or major bleeding episodes or the need to reduce the dose of warfarin.[97] Nevertheless, monitoring is reasonable in patients who are receiving concomitant antiplatelet or anticoagulant therapies.

In some patients, increases in alanine aminotransferase (ALT) levels without a concurrent increase in aspartate aminotransferase levels were observed. Therefore, ALT levels should be monitored periodically during omega-3 fatty acid therapy. Because of an increase in LDL-C levels observed in some patients treated with omega-3 fatty acids (the mechanism of which is not completely understood), LDL-C levels should be periodically assessed during treatment.[98] Omega-3 fatty acids should be used with caution in patients with sensitivity or allergy to fish.

Combination therapy with statins and omega-3 fatty acids. Few studies of combination therapies of omega-3 fatty acid and statins in patients with dyslipidemia have been published. Intuitively, one would assume that these therapies would have an additive effect, but no trials have been conducted in HIV-infected patients. Two clinical trials have demonstrated the safety and efficacy of omega-3 fatty acids and simvastatin in the general population.[99][100] However, drug interactions between antiretroviral drugs and lipid-lowering drugs need to be considered,[101] such as the use of simvastatin being contraindicated in patients receiving PI-containing regimens.[102]

Durrington and colleagues70 showed that omega-3 fatty acids were effective and safe in lowering triglyceride levels over 1 year in patients with CHD who had elevated triglyceride levels while receiving simvastatin treatment alone. The participants (n = 46) had established CHD and triglyceride levels higher than 2.26 mmol/L (higher than 200 mg/dL) despite maintenance therapy with simvastatin 10 to 40 mg/d. Those who received background therapy with simvastatin were randomized to omega-3 fatty acids 4 g/d or placebo for 24 weeks, followed by an open-label extension of active treatment for another 24 weeks. At 3, 6, and 12 months, omega-3 fatty acid treatment resulted in serum triglyceride level reductions of 20% to 30% (P < .005) and VLDL cholesterol level reductions of 30% to 40% (P < .005) compared with either baseline levels or levels seen in the placebo group. Changes were not related to simvastatin use. No increase in LDL-C level or decrease in HDL-C level was observed, and adverse events were mild.

McKenney and colleagues[103] conducted an open-label, randomized, 2-way crossover, drug-drug interaction study to evaluate single-dose and steady-state simvastatin kinetics in participants taking omega-3 fatty acids. The study consisted of two 14-day dosing periods separated by a washout period of at least 14 days. During the first 14-day dosing period, healthy volunteers (N = 24) were randomized to receive daily morning oral doses of either 4 g (4 capsules) of omega-3 fatty acids coadministered with 80 mg simvastatin (test treatment) or 80 mg simvastatin alone (reference treatment). During the second 14-day dosing period, participants received the alternative treatment. Omega-3 fatty acids did not appear to affect the pharmacokinetics of simvastatin after repeated dose administration, and they were safe and well tolerated.

Efficacy and Safety in HIV-Infected Patients

Wohl and colleagues9 conducted an open-label, randomized trial in which 52 patients were enrolled and received at least 3 antiretroviral agents. Fasting triglyceride levels were above 200 mg/dL. Patients received dietary and exercise counseling for 16 weeks, with or without omega-3 fatty acids (1750 mg of EPA and 1150 mg of DHA). Patients who received omega-3 fatty acids had a 25% mean reduction in fasting triglyceride levels at 4 weeks, compared with a 2.8% mean increase in patients receiving placebo (P = .007).

By 16 weeks, the mean reduction in triglycerides in patients receiving fish oil was 19.5%, whereas the mean decrease in patients not receiving fish oil was 5.7%, but the difference was not significant. LDL-C levels had increased by 15.6% at week 4 and by 22.4% at week 16 in the omega-3 fatty acid arm and by 3.5% and 18.4%, respectively, in the group not taking omega-3 fatty acids (P = .14).

To what extent the increase in LDL-C was attributable to the omega-3 fatty acids and whether this increase attenuates the beneficial effect of lowering triglyceride levels is not clear. The investigators concluded that given the benefits of reducing triglyceride levels with omega-3 fatty acids in HIV-infected patients, additional study of this therapy is appropriate.9

Manfredi and colleagues82 conducted a prospective, open-label assessment of the efficacy and safety of omega-3 fatty acids in HIV-infected patients with triglyceride levels of 250 to 500 mg/dL: 54 patients received omega-3 fatty acids, 53 received fibrates, and 49 were treated with diet and exercise only. Both omega-3 fatty acids and fibrates produced significant (P < .0001) reductions in mean triglyceride levels at 18 months, with fibrates showing a slightly more potent effect. Diet and exercise alone did not have a significant effect. Fourteen patients who received omega-3 fatty acids (26%) and 18 who received fibrates (34%) had normal triglyceride levels (less than 1.94 mmol/L [172 mg/dL]) by 18 months, which was not statistically significant.

Both omega-3 fatty acids and fibrates prevented the need to change antiretroviral regimens as a result of dyslipidemia. Fibrates were associated with a greater incidence of mild and transient GI disturbances than was lifestyle therapy or omega-3 fatty acids, although no discontinuations of therapy were required.[104]

Researchers in France randomized 122 HIV-positive patients to either two 1-g capsules of omega-3 fatty acid 3 times per day or placebo for 8 weeks, followed by 8 weeks of open-label omega-3 fatty acids for all patients.[105] Neither total cholesterol nor HDL-C levels changed over the course of therapy in either group, but triglyceride levels did decrease significantly (Table 3). Ten patients with baseline triglyceride levels above 10 g/L (greater than 1000 mg/dL) were given open-label omega-3 fatty acids. These patients also experienced a 35.6% mean reduction in triglyceride concentrations after 8 weeks, demonstrating in this study that omega-3 fatty acids are effective even in patients with very high triglyceride levels. Treatment was well tolerated. Taken together, these data indicate that omega-3 fatty acids reduce triglyceridemia in HIV-infected patients receiving antiretroviral therapy.

Omega-3 fatty acids have demonstrated anti-inflammatory effects, such as inhibition of cytokine production, that may have implications for immunomodulation. While one study has suggested that enteral nutritional supplementation enriched with omega-3 fatty acids may have beneficial effects on CD4 count and HIV-associated weight loss, the effect of omega-3 fatty acids on such measures has not been established.[107]

Combination therapy with fenofibrate. AIDS Clinical Trial Group A5186 evaluated the safety and efficacy of EPA (1.5 g) and DHA (0.91 g) twice a day in combination with fenofibrate (160 mg/d) in HIV-infected patients who had not responded adequately to either agent alone.[108] In this open-label, prospective study, 100 patients who were receiving antiretroviral therapy and had triglyceride levels above 4.52 mmol/L (400 mg/dL) were randomly assigned to fenofibrate or EPA and DHA. If the triglyceride level remained above 2.26 mmol/L (200 mg/dL) at 8 weeks, patients were given combination therapy.

The median baseline serum triglyceride level was 7.47 mmol/L (662 mg/dL) in the omega-3 fattyacid group and 7.83 mmol/L (694 mg/dL) in the fenofibrate group. During the first 8 weeks, omega-3 fatty acids and fenofibrate decreased serum triglyceride levels by 46% and 58%, respectively (P = .039). Four patients who received omega-3 fatty acids (8.5%) and 8 who received fenofibrate (16.7%) achieved the goal level; 75 participants (90.4%) proceeded to combination therapy. The median decrease in serum triglyceride levels from baseline to week 18 was 65% for patients participating in the combination phase of the study. The individual therapies and combination therapy were well tolerated and safe. Thus, the combination therapy may be appropriate in patients who cannot achieve adequate reductions with omega-3 fatty acids or fenofibrate alone.

Cardiovascular disease has emerged as an important public health concern among the HIV-infected population.[109][110][111][112][113] Smoking cessation and monitoring conditions such as diabetes and hypertension should be a component of risk reduction for the HIV-infected population.[114][115] Dyslipidemia as a result of HIV infection and its treatment has led to concern about elevated cardiovascular risk in these patients. Management of dyslipidemia in HIV-infected adults should follow the NCEP guidelines established for the non–HIV-infected population.[116] Although obtaining and maintaining virological control is the overriding concern in patients with HIV infection,[117] there may be a need for a shift in the health care model for persons with AIDS, from a primary focus on managing HIV infection to providing care that addresses all aspects of physical and mental health.[118]

The emergence of metabolic and lipid disturbances presents a pharmacological challenge because of the potential for drug interactions. Lipid-lowering drugs can be safely given to most HIV-infected patients. If the patient is experiencing only an elevation in LDL-C levels, a statin is first-line drug treatment. For the treatment of hypertriglyceridemia, the use of fibrates or omega-3 fatty acids may be considered. A prescription preparation of omega-3-acid ethyl esters was recently approved by the FDA for use in adults as an adjunct to diet to reduce triglyceride levels of 500 mg/dL or higher. Combination therapy with a statin and omega-3 fatty acids may be an alternative for treating combined dyslipidemia.

HIV-associated dyslipidemia is a modifiable risk factor for cardiovascular disease. Physicians should treat chronic diseases as aggressively in HIV-infected patients as in non–HIV-infected patients.[119] Judicious use of statins, fibrates, and omega-3 fatty acids—alone or in combination—may help control HIV-associated dyslipidemia. However, whether these approaches will decrease the risk of HIV-associated cardiovascular complications remains unclear at the present time. Additional research is needed to determine whether the metabolic complications that are associated with HIV infection and its therapies are different from the metabolic diseases (eg, diabetes and dyslipidemia) in the uninfected population.[120] Despite the need for clinical trials to establish the benefits of lipid-lowering agents in HIV-infected patients, these patients are appropriate candidates for all usual methods of risk reduction and health maintenance.[121][122]

Dr Metroka reports having received consultant fees from Reliant Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Gilead Sciences, and Tibotec Therapeutics and is an investigator for Tibotec Therapeutics and Bristol-Myers Squibb. Ms Truong reports having received consultant fees from Reliant Pharmaceuticals. Dr Gotto reports being a current member of the boards of directors of Aegerion Pharmaceuticals and Arisaph Pharmaceuticals; and a health advisory board member for DuPont; and having received consulting fees from Johnson & Johnson, Kowa Pharmaceuticals, Merck, Merck-Schering Plough, and Reliant Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.

Effect of essential fatty acid omega 3 on toll-like receptors in patients with severe multiple trauma.

Saturday, September 10th, 2011

Source

Department of Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China, 16750666@qq.com.

Abstract

This study examined the effects of ω-3 polyunsaturated fatty acid (ω-3PUFA) on the expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4) and some related inflammatory factors in peripheral blood mononuclear cells (PBMCs) of patients with early-stage severe multiple trauma. Thirty-two patients who were admitted to the Department of Traumatic Surgery, Tongji Hospital (Wuhan, China) between May 2010 and November 2010, and diagnosed as having severe multiple trauma with a injury severity score (ISS) no less than 16, were enrolled in the study and divided into two groups at random (n=16 in each): ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days. Peripheral blood from these patients was collected within 2 h of admission (day 0), and 1, 3, 5 and 7 days after the nutritional support. PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively, the levels of NF-κB by quantum dots-based immunofluorescence assay, the levels of TNF-α, IL-2, IL-6 and COX-2 by ELISA, respectively. The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support (both P<0.05). The levels of TNF-α, IL-2, IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day (P<0.05 for all). It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2, TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.

Long-Chain Omega-3 Fatty Acid Deficiency in Mood Disorders: Rationale for Treatment and Prevention.

Saturday, September 10th, 2011

Source

Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH 45219-0516, USA. robert.mcnamara@uc.edu.

Abstract

Major recurrent mood disorders including major depressive disorder (MDD) and bipolar disorder (BD) are associated with significant psychosocial morbidity and excess premature mortality primarily attributable to suicide and coronary heart disease. Limited efficacy and adverse side-effects associated with psychotropic medications used in the treatment of MDD and BD highlight the urgent need to develop safe and efficacious treatments or treatment adjuncts. A body of evidence now indicates that long-chain omega-3 (LCn-3) fatty acid deficiency is a feature associated with MDD and BD. The etiology of LCn-3 deficits in MDD and BD patients may be attributable to both genetic and environmental factors. Dietary LCn-3 supplementation is safe and well-tolerated with chronic administration and corrects LCn-3 deficiency in MDD and BD patients. LCn-3 supplementation has been found to augment the therapeutic efficacy of psychotropic medications in the treatment of mood symptoms and to reduce suicidality. Preliminary studies also suggest that LCn-3 supplementation is efficacious as monotherapy in the treatment and prevention of psychopathology in children and adolescents. LCn-3 supplementation may also be associated with reduced risk for developing coronary heart disease. The overall cost-benefit ratio associated with LCn-3 supplementation provides a strong rationale to diagnose and treat LCn-3 deficiency in MDD and BD patients, and to prevent LCn-3 deficiency in subjects at high risk for developing these disorders.

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