Do anti-tumour necrosis factor-α biologics affect subclinical measures of atherosclerosis and arteriosclerosis? A systematic review.

AIMS: Inflammatory cytokines, particularly tumour necrosis factor-α (TNFα), are thought to promote arterial disease through a variety of mechanisms leading to arteriosclerosis and atherosclerosis. We reviewed the existing evidence of the effect of anti-TNFα treatment on arteriosclerosis and atherosclerosis in chronic inflammatory disease. METHODS: We performed a systematic review of studies examining effects of monoclonal antibodies against TNFα on subclinical measures of arteriosclerosis (arterial pulse wave velocity) and atherosclerosis (endothelial function measured by flow-mediated dilation or forearm blood flow responses to endothelium-dependent agonists, and common carotid intima-media thickness). RESULTS: We identified 60 studies (of 854 potential studies identified using a systematic search) in which effects of anti-TNFα biologics on these measures were assessed in patients receiving anti-TNFα therapy for a clinical indication (usually an inflammatory disease such as an inflammatory arthritis, psoriasis or inflammatory bowel disease). Of these, only 6 were randomised clinical controlled trials. Whilst many observational studies and noncontrolled studies reported positive findings, positive finding were reported in only 1 of 6 randomised clinical controlled trials. CONCLUSIONS: There is no strong evidence for an effect of anti-TNFα biologics on the subclinical measures of arteriosclerosis or atherosclerosis examined in this review. This does not exclude a positive effect of TNFα biologics on clinical outcomes through alternate pathways including those induced by remission of the primary inflammatory disease.

Serum- and HDL3-serum amyloid A and HDL3-LCAT activity are influenced by increased CVD-burden.

BACKGROUND: High density lipoproteins (HDL) protect against cardiovascular disease (CVD). However, increased serum amyloid-A (SAA) related inflammation may negate this property. This study investigated if SAA was related to CVD-burden. METHODS: Subjects referred to the rapid chest pain clinic (n = 240) had atherosclerotic burden assessed by cardiac computerised tomography angiography. Subjects were classified as: no-CVD (n = 106), non-obstructive-CVD, stenosis<50% (n = 58) or moderate/significant-CVD, stenosis ≥50% (n = 76). HDL was subfractionated into HDL2 and HDL3 by rapid-ultracentrifugation. SAA-concentration was measured by ELISA and lecithin cholesterol acyltransferase (LCAT) activity measured by a fluorimetric assay. RESULTS: We illustrated that serum-SAA and HDL3-SAA-concentration were higher and HDL3-LCAT-activity lower in the moderate/significant-CVD-group, compared to the no-CVD and non-obstructive-CVD-groups (percent differences: serum-SAA, +33% & +30%: HDL3-SAA, +65% and +39%: HDL3-LCAT, -6% & -3%; p < 0.05 for all comparisons). We also identified a positive correlation between serum-SAA and HDL3-SAA (r = 0.698; p < 0.001) and a negative correlation between HDL3-SAA and HDL3-LCAT-activity (r = -0.295; p = 0.003), while CVD-burden positively correlated with serum-SAA (r = 0.150; p < 0.05) and HDL3-SAA (r = 0.252; p < 0.001) and negatively correlated with HDL3-LCAT-activity (r = -0.182; p = 0.006). Additionally, multivariate regression analysis adjusted for age, gender, CRP and serum-SAA illustrated that HDL3-SAA was significantly associated with modifying CVD-risk of moderate/significant CVD-risk (p < 0.05). CONCLUSION: This study has demonstrated increased SAA-related inflammation in subjects with moderate/significant CVD-burden, which appeared to impact on the antiatherogenic potential of HDL. We suggest that SAA may be a useful biomarker to illustrate increased CVD-burden, although this requires further investigation.

A questionnaire based survey study for the evaluation of knowledge of Pakistani University teachers regarding their awareness about ibuprofen as an over the counter analgesic.

In recent time, due to convenient availability of number of over the counter (OTC) drugs, patients are able to treat minor ailments by themselves. The self-medicated regimen has lead to certain health problems in all age groups irrespective of their professions. People are usually unaware about the safe use of NSAIDs (non-steroidal anti-inflammatory drugs) and currently there is no study carried out in COMSATS Institute of Information Technology (CIIT), Abbottabad, regarding the choice of faculty members for NSAIDs to relieve pain and their knowledge about its safety and use. A questionnaire based survey was carried out to collectdata about the choice of CIIT faculty for a specific NSAID and their cognition related to ibuprofen. Two hundred fifty faculty members (comprising of 53 pharmacy faculty members and 197 faculty members who belonged to other departments) of which 87 were females, took part in this study. Average age of participants was 34.86 +/- 9.02 years. Ibuprofen was the drug of choice NSAID among the participants. Four percent participants experienced pain almost every day. Analgesia was the well known indication for ibuprofen (31%) by both the groups and in general more educated and younger participants showed better apprehension related to indications. Sixty one percent participants comprising of non-pharmacy faculty were unaware of any undesirable effects and 79% (comprising of 72% pharmacists and 5% non-pharmacists) were affirmative that ibuprofen had no adverse effects. Fifteen percent participants of department other than pharmacy were not aware of any interactions of ibuprofen. 34% of participants (comprising of 32% non-pharmacists and 2% pharmacists) entrusted their physician for an analgesic. Regardless that many participants suffered from pain almost every day and their drug of choice would be ibuprofen, they had inadequate information related to the safety and use of ibuprofen.

Serum amyloid A-related inflammation is lowered by increased fruit and vegetable intake, while high-sensitive C-reactive protein, IL-6 and E-selectin remain unresponsive.

The present study assessed whether increased fruit and vegetable (F&V) intake reduced the concentrations of the inflammatory marker serum amyloid A (SAA) in serum, HDL2 and HDL3 and whether the latter reduction influenced any of the functional properties of these HDL subfractions. The present study utilised samples from two previous studies: (1) the FAVRIT (Fruit and Vegetable Randomised Intervention Trial) study - hypertensive subjects (systolic blood pressure (BP) range 140-190 mmHg; diastolic BP range 90-110 mmHg) were randomised to receive a 1-, 3- or 6-portion F&V/d intervention for 8 weeks, and (2) the ADIT (Ageing and Dietary Intervention Trial) study - older subjects (65-85 years) were randomised to receive a 2- or 5-portion F&V/d intervention for 16 weeks. HDL2 and HDL3 were isolated by rapid ultracentrifugation. Measurements included the following: serum high-sensitive C-reactive protein (hsCRP) by an immunoturbidimetric assay; serum IL-6 and E-selectin and serum-, HDL2- and HDL3-SAA by ELISA procedures; serum-, HDL2- and HDL3-cholesterol ester transfer protein (CETP) activity by a fluorometric assay. Although the concentrations of hsCRP, IL-6 and E-selectin were unaffected by increasing F&V intake in both studies (P>0·05 for all comparisons), those of SAA in HDL3 decreased in the FAVRIT cohort (P= 0·049) and those in HDL2 and HDL3 decreased in the ADIT cohort (P= 0·035 and 0·032), which was accompanied by a decrease in the activity of CETP in HDL3 in the FAVRIT cohort (P= 0·010) and in HDL2 in the ADIT cohort (P= 0·030). These results indicate that SAA responds to increased F&V intake, while other inflammatory markers remain unresponsive, and this leads to changes in HDL2 and HDL3, which may influence their antiatherogenic potential. Overall, the present study provides tangible evidence of the effectiveness of increased F&V intake, which may be of use to health policy makers and the general public.

α-Tocopherol induces proatherogenic changes to HDL2 & HDL3: an in vitro and ex vivo investigation.

INTRODUCTION: High density lipoproteins (HDL) have considerable potential for improving cardiovascular health. Additionally, epidemiological studies have identified an inverse relationship between α-tocopherol intake and cardiovascular disease, which has not been translated in randomised controlled trials. OBJECTIVES: This study assessed if increased α-tocopherol within HDL(2) and HDL(3) (HDL(2&3)) influenced their antiatherogenic potential. In the first of two in vitro investigations, the oxidation potential of HDL(2&3) was assessed when α-tocopherol was added following their isolation. In the second, their oxidation potential was assessed when HDL(2&3) were isolated from serum pre-incubated with α-tocopherol. Additionally, a 6-week placebo-controlled intervention with α-tocopherol assessed if α-tocopherol influenced the oxidation potential and activities of HDL(2&3)-associated enzymes, paraoxonase-1 (PON-1) and lecithin cholesteryl acyltransferase (LCAT). RESULTS: Conflicting results arose from the in vitro investigations, whereby increasing concentrations of α-tocopherol protected HDL(2&3) against oxidation in the post-incubated HDL(2&3), and promoted HDL(2&3)-oxidation when they were isolated from serum pre-incubated with α-tocopherol. Following the 6-week placebo-controlled investigation, α-tocopherol increased in HDL(2&3), while HDL(2&3) became more susceptible to oxidation, additionally the activities of HDL(2&3)-PON-1 and HDL(2)-LCAT decreased. CONCLUSION: These results have shown for the first time that α-tocopherol induces changes to HDL(2&3), which could contribute to the pathophysiology of cardiovascular disease.

The two faces of α- and γ-tocopherols: an in vitro and ex vivo investigation into VLDL, LDL and HDL oxidation.

BACKGROUND: Vitamin E and its derivatives, namely, the tocopherols, are known antioxidants, and numerous clinical trials have investigated their role in preventing cardiovascular disease; however, evidence to date remains inconclusive. Much of the in vitro research has focused on tocopherol's effects during low-density lipoprotein (LDL) oxidation, with little attention being paid to very LDL (VLDL) and high-density lipoprotein (HDL). Also, it is now becoming apparent that γ-tocopherol may potentially be more beneficial in relation to cardiovascular health. OBJECTIVES: Do α- and γ-tocopherols become incorporated into VLDL, LDL and HDL and influence their oxidation potential in an in vitro and ex vivo situation? DESIGN: Following (i) an in vitro investigation, where plasma was preincubated with increasing concentrations of either α- or γ-tocopherol and (ii) an in vivo 4-week placebo-controlled intervention with α- or γ-tocopherol. Tocopherol incorporation into VLDL, LDL and HDL was measured via high-pressure liquid chromatography, followed by an assessment of their oxidation potential by monitoring conjugated diene formation. RESULTS: In vitro: Both tocopherols became incorporated into VLDL, LDL and HDL, which protected VLDL and LDL against oxidation. However and surprisingly, the incorporation into HDL demonstrated pro-oxidant properties. Ex vivo: Both tocopherols were incorporated into all three lipoproteins, protecting VLDL and LDL against oxidation; however, they enhanced the oxidation of HDL. CONCLUSIONS: These results suggest that α- and γ-tocopherols display conflicting oxidant activities dependent on the lipoprotein being oxidized. Their pro-oxidant activity toward HDL may go some way to explain why supplementation studies with vitamin E have not been able to display cardioprotective effects.

Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance.

Obese subjects with impaired glucose tolerance (IGT) are more susceptible than healthy individuals to oxidative stress and cardiovascular disease. This randomised controlled investigation was designed to test the hypothesis that α-lipoic acid supplementation and exercise training may elicit favourable clinical changes in obese subjects with IGT. All data were collected from 24 obese (BMI ≥ 30 kg/m2) IGT patients. Following participant randomisation into two groups, fasting venous blood samples were obtained at baseline, and before and following intervention. The first group consisted of 12 participants who completed a 12 week control phase followed by 12 weeks of chronic exercise at 65% HRmax for 30 minutes a day, 5 days per week, while ingesting 1 gram per day of α-lipoic acid for 12 weeks. The second group consisted of 12 participants who completed the same 12 week control phase, but this was followed by 12 weeks of 1 gram per day of α-lipoic acid supplementation only (no exercise). The main findings show a comparatively greater rate of low density lipoprotein (LDL) oxidation in the group consisting of α-lipoic acid only (p < 0.05 vs. pre intervention), although total oxidant status was lower post intervention (p < 0.05 vs. baseline) in this group. However, exercise and α-lipoic acid in combination attenuates LDL oxidation. Furthermore, in the α-lipoic acid supplement plus exercise training group, total antioxidant capacity was significantly increased (p < 0.05 vs. baseline and pre intervention). Body fat percentage and waist and hip circumference decreased following exercise training (p < 0.05 vs. post intervention). There were no selective treatment differences for a range of other clinical outcomes including glycaemic regulation (p > 0.05). These findings report that α-lipoic acid ingestion may increase the atherogenicity of LDL when ingested in isolation of exercise, suggesting that in IGT the use of this antioxidant treatment does not ameliorate metabolic disturbances, but instead may detrimentally contribute to the pathogenesis of atherosclerosis and development of CVD. However, when α-lipoic acid is combined with exercise, this atherogenic effect is abolished.