Cholesterol How To Reduce

Lower Your Cholesterol Ebook

Discover how to lower your cholesterol in a natural, safe and painless way with Scott Davis Beat Cholesterol in 30 Days. In this revealing e-book, you will find out how to get rid of those expensive cholesterol medications (which Scott says are only making your condition worse), how to eat deliciously and still beat cholesterol, and how to gain confidence and ultimately cut the risk of having a heart attack. This program reveals to people some main factors that cause their hypercholesterolemia such as smoking, high blood pressure, diabetes, obesity, and family history of heart disease. The program also covers tips to prevent the recurrence of hypercholesterolemia such as eating a low-fat and low-salt diet, stopping smoking, losing extra pounds, and maintaining a healthy weight. Davis believes so much in the results of this test that he is offering a no-risk guarantee when you buy his e-book. If for any reason you arent satisfied in the first 60 days you can get your money back. At the very worst, even if you dont learn anything new from this e-book you will get your money back. Continue reading...

Natural Cholesterol Guide Summary


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My Natural Cholesterol Guide Review

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Lipids Triglycerides Phospholipids Steroids

Triglycerides and phospholipids have an important part of their chemical anatomy in common they both contain fatty acid tails that are strongly hydrophobic (high-droh-FOH-bik) or ''water'' (hydr) ''hating'' (phobic). Each triglyceride molecule has ''three'' (tri-) fatty acid tails attached to a three-carbon molecule called glycerol (GLIH-ser-ahl). Triglycerides make up most of the body fat we humans store as extra energy within some of our cells and tissues. Hundreds of triglyceride molecules tend to group together and form sphere-shaped fat droplets.

Mechanism Of Action Of Statins

Statins are competitive inhibitors of HMG-CoA reductase which converts HMG-CoA to mevalonate. This enzyme is recognised to be the rate limiting enzyme in the cholesterol biosynthetic pathway (Fig. 1). Analysis of the human genome has shown that there is only one gene for HMGCoA reductase which is found in all cell types. The enzyme is anchored in the endoplasmic reticulum through the amino terminal part of the protein which comprises 8 transmembrane spanning domains (Fig. 2).

Searching for Alzheimers Disease Therapies In Your Medicine Cabinet The Epidemiological and Mechanistic Case For NSAIDs

Despite this bleak clinical picture, an intriguing story has emerged in recent years from epidemiological studies asking whether the use of any currently marketed drugs is associated with a decreased risk of AD. Two classes of drugs have consistently emerged in the affirmative for this question. The first are the nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used either acutely in the treatment of mild to moderate pain, swelling, and fever, or more chronically in the treatment of rheumatoid arthritis. The second is a class of popular cholesterol-lowering drugs known collectively as statins, used as a primary preventative to block the development of atherosclerosis. This epidemiological record has spawned a growing literature that seeks to explore the mechanisms by which both of these classes of drugs might have their purported protective effects in AD. Since observational epidemiological studies do not prove causality, large placebo-controlled clinical trials in AD patients...

The Influence of Dietary Fats on Blood Cholesterol Levels and Distribution of Fatty Acids

Blood cholesterol levels and risk of cardiovascular disease are influenced by dietary intakes of fats. The intake of red meats and saturated fats are a primary cause of elevated blood cholesterol levels.25 Monounsaturated fats generally have a neutral effect on cholesterol, whereas polyunsaturated fats decrease cholesterol levels.26 Dietary cholesterol can increase blood cholesterol levels, but contributes less to blood cholesterol levels than saturated fats.13 Specific fatty acids within each major class, saturated, monounsaturated, and polyunsaturated, often have unique effects on blood cholesterol levels and should be considered on an individual basis. Palmitic acid, a 16-carbon saturated fatty acid, is a major contributor of saturated fat intake in the United States diet, accounting for greater than 60 of the saturated fat intake. It is associated with an elevation in LDL levels27 and may cause these elevated levels by inhibiting the expression of LDL receptors on cell surfaces.28...

Pleiotropic Effects of Statins

The word 'pleiotropic' usually is applied to genetics, referring to the multiple actions of a single gene. With regard to statin therapy for dyslipidemia, the term has become synonymous with clinical benefits of statins beyond the effects on lipoproteins. Hypercholesterolemia is strongly associated with coronary and vascular atherosclerotic disease. Atherosclerosis is mediated, in part, by the uptake of modified low-density lipoprotein (LDL) into the vessel wall. The predominant mechanism underlying the beneficial effects of statins is the inhibition of the enzyme HMG-CoA, thus blocking the early rate-limiting step in cholesterol biosynthesis. Therapeutic doses of statins reduce serum total and LDL cholesterol levels markedly in humans. without a significantly high cholesterol level. This has led to the hypothesis that statins may exert protective effects beyond cholesterol reduction. This was first noted in the subgroup analyses of the West of Scotland Coronary Prevention Study...

Mechanistic Basis of the Efficacy of Statins in Atherothrombosis

In addition to their well-documented effects on serum lipid levels, there are several other postulated mechanisms by which statins exert a variety of beneficial effects on the determinants of atherothrombosis. These effects are summarized in table 1. Most of these effects have been attributed to the modification of the altered biology of endothelial cells and vascular SMCs as well as coagulation and platelet activation pathways. In particular, statins enhance the activity of endothelial nitric oxide synthase (eNOS) and thereby the biosynthesis of the potent vasodilator and platelet inhibitor NO in vascular endothelial cells 5 . Statins also prevent degradation of NO by inhibiting the generation of oxidant species. Statins inhibit pre-proET-1 mRNA expression and reduce ET-1 release in bovine endothelial cells 6 . Recent studies show that statins decrease angiotensin II type 1 receptor expression in SMCs which is another potent vasoconstrictor and pro-fibrotic stimulus 7 . In addition,...

Relevant Vascular Effects of Statins

High cholesterol levels initiate endothelial activation followed by its dysfunction, which is observed even before plaque formation. Endothelial activation and dysfunction may relate to the decreased bioavailability of vasodilators such as NO, and or excess of vasoconstrictors such as endothelin. High cholesterol concentrations are responsible for endothelial activation, since endothelial function promptly improves after plasma LDL aphaeresis. This may explain the beneficial effects of statins which have a potent LDL-lowering property. However, in some studies restoration of endothelial function occurred even before a significant reduction in serum cholesterol levels was evident, suggesting that there are also cholesterol-independent effects of statins by which endothelial function improves 20 . Improvement in NO release with statins is associated with upregulation of eNOS mRNA and improvement of endothelial function. Since statins also increase NO production in humans at clinically...

Statins and Blood Pressure

Interactions between dyslipidemia and activation of neurohumoral systems, such as RAS, may not only explain the frequent coexistence of hypertension and dyslipidemia, but also play an important role in the pathogenesis of atherosclerosis. Experimental data suggest that the effects of Ang II and lipo-proteins on atherogenic risk are not independent and that the pathways by which Ang II and dyslipidemia lead to vascular disease may frequently overlap. There is a suggestion that the combined use of cholesterol-lowering drugs along with agents that modulate RAS may have additive benefits in the prevention and treatment of coronary artery disease, hypertension, and heart failure. Keidar et al. 30 harvested macrophages from the peritoneum after injection of Ang II in the rat, and observed that Ang II dramatically increased macrophage cellular cholesterol biosynthesis with no significant effect on blood pressure or on plasma cholesterol levels. Fosinopril and the AT1 receptor blocker...

Familial Hypercholesterolemia

Secretory Vesicles Electron Micrograph

The significance of LDL receptors and receptor-mediated endocytosis is illustrated by a hereditary disease called familial hypercholesterolemia.31 People with this disease have an abnormally low number of LDL receptors. Their cells therefore absorb less cholesterol than normal, and the cholesterol remains in the blood. Their blood cholesterol levels may be as high as 1,200 mg dL, compared to a normal level of about 200 mg dL. People who inherit the gene from both parents typically have heart attacks before the age of 20 (sometimes even in infancy) and seldom survive beyond the age of 30.

Goodand Bad Cholesterol

Functional Groups Cholesterol

There is only one kind of cholesterol, and it does far more good than harm. When the popular press refers to good and bad cholesterol, it is actually referring to droplets in the blood called lipoproteins, which are a complex of cholesterol, fat, phospholipids, and protein. So-called bad cholesterol refers to low-density lipoprotein (LDL), which has a high ratio of lipid to protein and contributes to cardiovascular disease. So-called good cholesterol refers to high-density lipoprotein (HDL), which has a lower ratio of lipid to protein and may help to prevent cardiovascular disease. Even when food products are advertised as cholesterol-free, they may be high in saturated fat, which stimulates the body to produce more cholesterol. Palmitic acid seems to be the greatest culprit in stimulating elevated cholesterol levels, while linoleic acid has a cholesterol-lowering effect. Both are shown in figure 2.19. Cardiovascular disease is further discussed at the end of chapter 19, and LDLs and...

Effects of Statins on Vascular Elasticity

Evidence for blood pressure-lowering effect of statins Table 2. Evidence for blood pressure-lowering effect of statins Statins (pravastatin or simvastatin) in addition to antihypertensive treatment Additive benefit of statins in lowering blood pressure Intensive cholesterol reduction with atorvastatin reduced large artery stiffness and blood pressure in normo-cholesterolemic patients with stage I isolated systolic hypertension The effects of statins on endothelium have been amply described, and include an increase in eNOS expression (and activity). Statins also reduce the generation of oxidant species in endothelial cells. These effects appear to be dose-dependent and are shared by all statins with minor inter-statin variability. Schmalfuss et al. 41 , in our laboratory, examined the effects of different statins on vascular endothelial cell growth. Whereas atorvastatin and simvas-tatin reduced endothelial cell growth in culture, pravastatin did not affect it. Increase in...

Nonldl Cholesterol Lowering Actions Of Statins

The efficacy of statins in lowering serum LDL cholesterol is well-recognised 2-4 . The widespread clinical use of statins has led to observations that statins have additional effects not explicable through their primary role of lowering serum LDL cholesterol. Initial clinical trial data in patients with hypercholesterolemia indicated beneficial effects of statins on cardiovascular parameters beyond that expected for their ability to directly lower LDL cholesterol 3,27-31 . There is now clear-cut evidence that statins act locally on the vascular wall to directly reduce inflammation. Additional anecdotal clinical data has emerged from trials to suggest that statins benefit other disease processes. Epidemiological data hinted that statins may influence the incidence and severity of transplant rejection episodes, progression of Alzheimers dementia (AD), the incidence of hip fracture and, possibly neoplasia (see below). Although the clinical trial data remains equivocal, studies to explore...


As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10 3,16 . The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10 vs. 2-6 ) 16,24 . Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis 25 and decrease apoB-containing lipoproteins 26 . A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and...

Advanced revascularization strategies and angiogenesis

Our group investigated the effect of endothelial dysfunction secondary to hypercholesterolemia on therapeutic angiogenesis. In a pig model of chronic myocardial ischemia, animals were fed either a high-cholesterol or a normal diet. Four weeks after placement of an ameroid constrictor on the left coronary circumflex artery, FGF-2 loaded in heparin alginate beads for slow release was implanted in the circumflex territory. The hypercholesterolemic group showed significant endothelial dysfunction and impaired angiogenesis manifest as decreased circumflex perfusion compared to the control, normal diet group. FGF receptor-1 expression was upregulated in the control group, but decreased in the hypercholesterolemic animals (54). Decreased production of growth factors may contribute to a lack of compensatory neovascularization in some patients with ischemic cardiovascular disease.

The development of oxidative rancidity in foods

Lipids occur in nearly all food raw materials with the major classes being triglycerides (also known as triacylglycerols), which occur in fat storage cells of plants and animals, and phospholipids, which occur in biological membranes. In the processing of a wide range of foods, fats may be added as part of the food formulation. The added fats are a major component of many foods including mayonnaise, margarine, and frying oils. These fats are almost completely triglycerides, and it is these components that are of most significance as potential sources of oxidative off-flavours in these foods. In plant or animal tissues used as foods, the phospholipids present in all biological membranes may be an important substrate for oxidative deterioration. The spontaneous reaction of atmospheric oxygen with lipids, known as autoxidation, is the most common process leading to oxidative deterioration. Polyunsaturated fatty acids have the potential for decomposing by this process, whether they are...

The Development of New Antibiotics Is Slowing

For many years, pharmaceutical companies developed new antibiotics to replace old ones whose effectiveness was seriously reduced by resistance. The new drugs were often more potent versions of earlier compounds. Unfortunately, finding completely new antibiotic classes becomes progressively more difficult as we exhaust the available drug targets in pathogens. Early in the Twenty-First Century, pharmaceutical companies placed considerable hope on genomic technology as a way to find new bacterial drug targets and thereby new antibiotics. In this approach, computer-based analyses examine the information in bacterial DNA and gene expression profiles to identify potential targets for new antibiotics. So far, that approach has not panned out. At the same time, pharmaceutical executives realized that more money could be made from quality-of-life drugs and drugs for managing chronic diseases. For example, heart disease requires life-long therapy to lower cholesterol. In contrast, antibiotics...

Adiponectin Deficiency and Cardiovascular Diseases

Adiponectin is inversely correlated with a panel of traditional cardiovascular risk factors, including blood pressure, heart rate, and total and low-density lipoprotein (LDL) cholesterol and triglyceride levels, and is positively related to high-density lipoprotein (HDL) cholesterol levels (80,81). Hypoadiponectinemia has been shown to be an independent risk factor for endothelial dysfunction and hypertension, regardless of insulin resistance (82,83). In addition, the association of hypoadiponectinemia with coronary heart disease (84), ischemic cerebrovascular disease (85), and coronary artery calcification (86) was also reported to be independent of classical cardiovascular risk factors, such as diabetes, dyslipidemia, and hypertension.

Classification and evolution of increased cardiometabolic risk states

Dyslipidemia high triglycerides, low HDL, small dense LDL* Figure 1.2 The current perspective on the relationship between metabolic syndrome and coronary heart disease. The presence of obesity in an individual is highly associated with the development of insulin resistance and hyperinsulinemia. Many traditional risk factors for CVD are related to the development of metabolic syndrome and these include glucose abnormalities, dyslipid-emia and hemodynamic factors. However, novel risk factors such as abnormalities in inflammatory markers, i.e. C-reactive protein (CRP) and coagulopathy (plasminogen activator inhibitor-1 (PAI-1)) also appear to play a role. BMI, body mass index HDL-C, high-density lipoprotein cholesterol LDL, low-density lipoprotein PHLA, postheparin lipolytic activity PP, postprandial SNS, sympathetic nervous system TG, triglycerides. These factors are highly related to the development of coronary heart disease. From reference 17, with permission on insulin resistance as...

Mechanism of lipoxygenasecatalysed oxidation

Lipoxygenase activity requires the presence of free polyunsaturated fatty acids. Linoleic acid is the most common substrate in plant foods. The enzyme occurs in a variety of isozymes, which often vary in optimum pH, as well as product and substrate specificity. Four isozymes have been isolated from soybeans. Soy isozyme 1 has an optimum pH of 9.0. It only acts on free polyunsaturated fatty acids and it forms 9- and 13-hydroperoxides in the ratio of 1 9 at room temperature. Soy isozyme 2 has an optimum pH of 6.8, it acts on triglycerides as well as free polyunsaturated fatty acids and it forms 9- and 13-hydroperoxide in the ratio of about 1 1 at room temperature. Soy isozyme 3 is similar to isozyme 2, but its activity is inhibited by calcium ions, whereas lipoxygenase 2 is stimulated by the metal. Lipoxy-genase 4 is very similar to isozyme 3, but can be separated by gel chro-matography or electrophoresis. Lipoxygenase isozymes are commonly classified as type 1, which have an optimum pH...

Adipose tissue as a dynamic endocrine and paracrine organ

The primary role of adipose tissue has been related to its ability to store triglycerides during periods of positive energy balance and to mobilize this reserve when expenditure exceeds intake. Adipose tissue is a special loose connective tissue composed not only of adipocytes, but also of other cell types, termed the stromavascular fraction, comprising

FDA Perspectives of Biomarkers

These include the following an epidemiological basis, supportive evidence in animal models, a demonstration that the effect of treatment on the biomark-er is consistent across multiple drug classes, and that the change in biomarker parallels that of the disease and impacts disease outcome. Thus, in support of LDL-c as an acceptable biomarker, lower total-c levels are associated with a reduced CHD mortality rate 113 the work of Brown and Goldstein demonstrated in a human disease, familial hypercholesterolemia, a linkage with LDL receptor defects and cholesterol levels 114 a variety of animal models demonstrate a linkage between LDL-c and atherosclerosis 115 and clinical trials that demonstrate benefits of LDL-c reduction, by multiple mechanisms including diet, niacin and most rigorously, statin treatment 116, 117 .

Nicotinic Acid Receptor Agonists 21 Niacin

Niacin, 1, (nicotinic acid) has been used clinically since 1955 for the treatment of dyslipidemias. Niacin therapy has a beneficial effect on all blood lipid parameters, resulting in lower triglycerides, lower VLDL LDL and increased HDL. The exact mechanism by which niacin exerts this effect is not precisely understood but it is known that administration of niacin reduces cAMP levels in adipocytes thereby inhibiting lipolysis by hormone sensitive lipase. The resulting decrease in free fatty acid release by adipocytes leads to decreased hepatic triglyceride synthesis and VLDL production. VLDL is the primary recipient of cholesteryl esters originating in HDL and transferred by the cholesteryl ester transfer protein. It is postulated that HDL-C levels increase as the amount of VLDL acceptor diminishes. Recently, a G-protein coupled receptor - termed HM74A - was identified as the high affinity target of niacin by three separate groups 19-21 . The reported dissociation constants for niacin...

Cetp Inhibitors 31 Background

Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl esters (CE) and triglycerides (TG) among lipoprotein particles. The process is driven by the substrate concentration gradient between the lipoproteins, and the net effect is the transfer of cholesteryl esters from the CE-rich HDL particles primarily to VLDL and the reciprocal movement of triglycerides from TG-rich VLDL particles to HDL. It has been postulated that CETP is pro-atherogenic as it directly decreases plasma HDL-C and increases LDL-C. Genetic studies of populations with reduced or absent CETP expression show markedly increased HDL-C levels but have yielded contradictory evidence as to whether the diminished CETP activity results in fewer cardiac events. It has been established in clinical studies that pharmacological inhibition of CETP results in increased plasma HDL-C concentrations, although the effect of this inhibition on coronary heart disease has yet to be determined. The use of CETP...

Indo Mediterranean Diet Heart Study

It is noteworthy that approximately 60 of calories came from carbohydrates, of which a substantial proportion was presumably from fruit, vegetable, and grain consumption. In contrast to the Lyon Diet Heart Study, consumption of the Indo-Mediterranean diet resulted in significant reductions in total and LDL cholesterol, and an increase in HDL-cholesterol. In addition, blood pressure and body mass index were reduced with the Indo-Mediterranean diet compared to controls. A common feature of both the Lyon Diet Heart study and Indo-Mediterranean Diet Heart study was the emphasis on ALA consumption. In the latter study, increased consumption was achieved by emphasizing foods and oils rich in ALA (nuts, soybean oil, and mustard seed oil).

Agents With Unspecified Mechanisms

Triglycerides of 91 relative to pretreatment values 66 . Additionally, 29 was shown to inhibit fatty acid and sterol synthesis in rat hepatocytes and in vivo and it was proposed that this inhibition of lipid synthesis at least partially explains the beneficial effect of these compounds on lipid profiles. More recently, the series was extended to a-cycloalkyl-rn-keto dicarboxylic acids and analog 30, when tested in obese Zucker fatty rats as described above, led to an increase in HDL-C of 171 and a decrease in triglycerides of 94 relative to pretreatment values 67 . Compound 30 also showed inhibition of fatty acid synthesis in rat hepatocytes.

Effects Of Microbial Contamination On Milk Quality

The presence and growth of bacteria in milk affects milk quality. Chemical components of milk can be degraded by bacterial metabolism and various enzymes secreted by bacteria. Products of these degradation reactions can have undesirable effects on milk structure, smell, and taste. Lactose present in milk is readily fermented by lactic acid bacteria, resulting in sour flavor notes and, if the pH of milk drops below 4.6, precipitation of casein proteins (Bylund, 1995 Jay, 2000). Fermentative metabolism of lactose by a variety of bacteria can also produce numerous volatile compounds, including acetic and butyric acids, carbon dioxide and hydrogen gas, and various alcohols that can adversely affect milk odor and flavor. Proteins are also subject to degradation by bacteria and their secreted enzymes. Digestion of proteins by extracellular proteases can create bitter-tasting peptides cause curdling and clotting of the milk result in production of ammonia and hydrogen sulfide and ultimately...

Vitamin E In Diabetes

About one-half of the total plasma vitamin E is a constituent of circulating LDL. Interindividual variations in plasma vitamin E are closely related to those in LDL (24,25). The concentration of vitamin E per LDL particle is rather low (i.e., in the order of 5-9 molecules compared with 2200 molecules of cholesterol and 170 molecules of triglycerides) (26). Nevertheless, the level of vitamin E in LDL is an independent factor that influences susceptibility of LDL to oxidation. The lagtime of in vitro LDL oxidation was found to be related to the level of vitamin E in LDL when diabetic patients were supplemented with vitamin E (27,28). For persons with usual nutritional habits, the corresponding relationship was observed in two studies (29,30) but not in others (3,31,32).

Problem With Lipid Standardization Of Vitamin E

There are close correlations between the concentrations of vitamin E and lipids (triglycerides, cholesterol, and phospholipids) in plasma. They are due to the lipophilic properties of vitamin E, and moreover they reflect that the antioxida-tive capacity of lipids is regulated in progression with the lipid mass. -2.9 (cholesterol -5.2) -1.5 (triglycerides -1.3)

Potential Therapeutic Applications

The first results of phase III clinical studies of rimonabant in obesity were presented in March 2004 79,80 . 1036 overweight or obese patients (BMI between 27 and 40kgjm2) with untreated dyslipidemia (high triglycerides and or low HDL cholesterol) were randomized to receive either a daily, fixed dose of rimonabant (5 or 20 mg) or placebo along with a mild hypocaloric diet. Patients treated for one year with rimonabant (20 mg per day) lost 8.6 kg (versus 2.3 kg in the placebo group). In addition to weight loss, the study was designed to assess a number of important associated cardiovascular risk factors. Rimonabant (20mg) was associated with a significant reduction in waist circumference, triglycerides and C-reactive protein and an increase in HDL-cholesterol. Importantly, the number of patients classified as having metabolic syndrome 81 was reduced from 52.9 at baseline to 25.8 at one year 82 . These robust data were replicated in another phase III study (RIO-Europe) involving 1507...

Acc Inhibitors In Longterm Efficacy Studies

The second study with 2 was performed in diet-induced obese (DIO) C57Bl6 J mice. Compared to control DIO mice, mice treated with 2 showed significantly less weight gain over the course of the 6-week study. However, mice treated with 2 had liver triglyceride and total cholesterol levels that were identical to untreated DIO mice. In a glucose infusion clamp study, the glucose infusion rate was slightly higher for the treated animals ( 10 ) than for the untreated DIO mice. The study concluded that treatment with 2 had a moderate effect on improving the diabetic phenotype of DIO mice 49 .

Alkaline reflux gastritis syndrome

No specific medical therapy is available for alkaline reflux gastritis. Prokinetic agents, proton pump inhibitors, H2 antagonists, and cholestyramine all have inconsistent results. Roux-en-Y biliary diversion is the treatment of choice. Vagotomy, if not performed earlier, is done to prevent marginal ulceration. Some surgeons recommend adding subtotal gastrectomy to speed gastric emptying. Jejunal interposition between the gastric remnant and the duodenum has also been successfully used to treat this condition.

Postvagotomy Diarrhea Syndrome

Vagal innervation is an important factor in the control of pancreaticobiliary secretion and intestinal absorption. Truncal vagotomy may result in excessive small bowel secretions or bile acids with resulting diarrhea. Diarrhea occurs in up to 25 of patients following a complete (truncal) vagotomy with gastric drainage or resection (17). Less than 2 of patients have incapacitating symptoms. The syndrome is characterized by frequent watery stools, usually unrelated to meals, and occurring at night. Medical therapy includes dietary alterations with low fluid content, frequent feedings, increasing dietary fiber, and adding substances such as pectin to slow intestinal transit. Medications include cholestyramine, which may help bind bile salts, and somatostatin, which is effective in some patients. Surgical therapy is rarely recommended, but when needed, consists of interposition of a 10 cm antiperistaltic jejunal limb 100 cm distal to the ligament of Treitz (18).

Observational Epidemiology

These results were consistent with the Health Professionals Follow-up Study (HPFS), an observational study of nearly 40,000 US male health professionals aged 40-75 years who did not have CHD, diabetes, or hypercholesterolemia.22 After adjustment for cardiac risk factors, the relative risk (RR) of CHD for those in the highest vs. lowest quintile of vitamin E intake was 0.60 (95 confidence interval (CI) 0.44-0.81 P for trend 0.01). Further analysis revealed that the protective association was strongest for vitamin E consumed in supplements. Men who took at least 100 IU per day for at least 2 years had a multivariate RR of 0.63 (95 CI, 0.47-0.84) for CHD compared with men who did not take vitamin E supplements. A weak association was found for dietary vitamin E intake alone among men who did not take vitamin supplements, the RR comparing the extreme quartiles was 0.79 (95 CI, 0.54-1.15, P for trend 0.11).

Vitamin E Primary Prevention Trials

The Primary Prevention Project (PPP) was an open-label 2 x 2 factorial trial of vitamin E (300 mg d) and low-dose aspirin in 4,495 Italian men and women with one or more of the following CVD risk factors hypertension, hypercholesterolemia, diabetes, obesity, family history of premature MI, or age 65 years.32 Since there was convincing evidence that aspirin was beneficial, the trial was stopped early after a mean follow-up of 3.6 years. At that time, vitamin E had no effect on any prespecified endpoint including the main combined endpoint of CVD death, nonfatal MI, and nonfatal stroke (RR 1.07 95 CI, 0.74-1.56). The negative result may have been due to insufficient statistical power or inadequate dosing of vitamin E.

Adipocyte Dysfunction And Insulin Resistance

Our understanding of fat and carbohydrate metabolism and their interaction. In particular, a large body of evidence has accumulated suggesting that PPARy is a master regulator in the formation of fat cells and their ability to function normally in the adult21,22. PPARy is induced during adipocyte differentiation and ectopic expression of PPARy in non-adipogenic cells effectively converts them into mature adipocytes23,24. Thus, the discovery and study of the PPARs have contributed greatly to the evidence supporting the role of the adipocyte as having a major effect on skeletal muscle glucose uptake. First, there is evidence that activation of PPARy in adipose tissue improves its ability to store lipids, thereby reducing 'ectopic' fat storage in liver and muscle21. If this metabolic pathway is activated, lipid repartitioning on a whole-body level will occur increasing the triglyceride content of adipose tissue, lowering free fatty acids and triglycerides in the circulation, liver and...

Vitamin E Secondary Prevention Trials

Group having more men, lower total cholesterol levels, lower systolic blood pressures, and fewer diabetics. There is no clear explanation for the striking difference in results for nonfatal MI and CVD death. CHAOS was the first large prospective clinical trial to produce some results in favor of the oxidation theory in atherosclerosis. The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9,541 participants with CVD or diabetes and at least one other CVD risk factor (hypertension, hypercholesterolemia, smoking, low HDL, or microalbuminuria) into a study of vitamin E (400 IU daily), the angiotensin-converting enzyme inhibitor ramipril, both agents, or neither.45 The study was stopped early after a mean follow-up of 4.5 years because of the beneficial effects of ramipril. Vitamin E had no effect on the primary combined endpoint of MI, stroke, and CVD death (RR 1.05 95 CI, 0.95-1.16), and secondary analysis of various CVD endpoints (e.g., unstable angina, revascularization)...

Triglyceride Synthesis

The small intestine is the site of significant triglyceride synthesis in humans, as 95 of the body's lipid is derived from dietary fat 22 . Through the mono-acylglycerol pathway, dietary lipids entering the small intestine are hydrolyzed by lipases to free fatty acids and monoacylglycerols in the lumen. These are absorbed by enterocytes, the cells that form the luminal lining of the small intestine. Within enterocytes, fatty acids and monoacylglycerols are recombined by a series of sequential esterification steps involving acylCoA monoacyl glycerol acyltransferase (MGAT) and DGAT. The triglycerides are then incorporated into nascent chylomicrons, which are secreted from the enterocytes into the lymphatic system. DGAT is required for the production of triglycerides upon absorption of nutrients from the gut, as well as triglycerides produced via de novo lipogenesis, and thus represents the sole enzyme common to both pathways 23 .

Fatty Acid Synthesis And Metabolism

ACC1 homozygous knockout mice are embryonically lethal 45 , while ACC2 homozygous knockout mice are healthy and exhibit favorable metabolic pheno-types, such as increased fatty acid oxidation, reduced hepatic triglyceride content, and decreased body weight despite increased food intake 46 . Studies using liver-selective antisense oligonucleotides targeting ACC1 and ACC2 in a diet-induced fatty liver rat model have demonstrated that selective suppression of either ACC1 or ACC2 had moderate or no effect on lipogenesis, whereas suppression of both ACC1 and ACC2 stimulated fatty acid oxidation, lowered hepatic triglycerides, and improved insulin sensitivity 47 . Bipiperidylcarbox-amide CP-640186 (14) is an isoform non-selective ACC inhibitor (IC50 60nM). In Hep-2G cells (hepatocytes), 14 lowered fatty acid synthesis, TG synthesis, TG secretion, and apo-B secretion without affecting cholesterol synthesis. In addition, 14 increased fatty acid oxidation in mouse muscle cells. Treatment of ob...

Scope And Limitations Of Marketed Therapies

Despite a large body of evidence supporting the atheroprotective benefits of HDL, drugs available on the market that raise HDL are limited. Amongst the marketed drugs, the statins offer only marginal increases (5-10 ), while fibrates elevate HDL levels by 10-15 . As indicated in Table 1, agents belonging to these classes have primarily been used to modulate LDL and TGs respectively. Of the Statins 3,16

Endothelial Regulation of the Coronary Microcirculation

Factor, endothelin, and reactive oxygen species. Among these various factors, NO plays a predominant role. The enzyme responsible for production of NO is eNOS (or NOS-3), a 133-kDa protein constitutively expressed by endothelial cells. The biochemical mechanisms responsible for function of the NO synthases have recently been elucidated. For all isoforms, an electron donor (nicotinamide adenine dinucleotide phosphate, or NADPH) binds to a site at the carboxyl terminus of the protein. Electrons are then transferred from NADPH to the flavins flavin-adenine dinucleotide (FAD) and flavin mononucleotide (FMN) noncovalently bound within the reductase domain. For the neuronal NOS and eNOS, electrons are stored on the flavins until the enzyme is activated by calcium calmodulin (Ca CaM). When calmodulin binds to the enzyme, electrons are transferred to a prosthetic heme group in the oxygenase domain. Upon heme reduction, catalysis of arginine to citrulline and No occurs. The No thus formed...

Nuclear Receptor Based Lipid Mediators

Nuclear Hormone receptors There are several nuclear hormone receptors which are involved in the regulation of lipid metabolism. The liver X receptors (LXR), retinoid X receptors (RXR), and farnesoid X receptors (FXR) are activated by oxysterols, retinoids, and bile acids, respectively. RXR also forms heterodimers with peroxisome proliferator-activated receptors alpha, delta, and gamma (PPARs), with LXR alpha and beta, and FXR. All of these nuclear receptors have been targeted for drug development (40). Fibrates (e.g. fenofibrate, 17) are agonists of PPAR alpha, which results in the induction of a series of genes leading to a reduction in plasma triglyceride levels and an increase in HDL-cholesterol. The glitazones (e.g. rosiglitazone 18 and troglitazone 19) are agonists of PPAR gamma, which improve insulin sensitivity and are used as oral hypoglycemic agents. A high affinity PPAR gamma agonist, GI262570, 20 (pKi 8.9), has been reported to have potent antihyperglycemic effects as well...

Other Lipoprotein Mediators

Vascular Protectants - The compound AGI-1067, 30, has been reported to inhibit atherosclerosis in apo E and LDL receptor knockout mice (61, 62). AGI-1067 is an anti-inflammatory, lipid-lowering compound, that has been shown to selectively inhibit cytokine induced vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemotactic protein 1 (MCP-1) expression in vitro and in vivo. AGI-1067 lowers plasma cholesterol levels in cholesterol-fed mice and apo E knockout mice. In LDL receptor knockout mice, AGI-1067 inhibited atherosclerosis without lowering plasma cholesterol levels. These results indicate that AGI-1067 lowers plasma cholesterol through enhanced LDL receptor mediated lipoprotein clearance and that this compound has a direct anti-atherosclerosis vascular protectant activity. AGI-1067 has progressed to clinical trials and may be The current pharmacological focus for clinical treatment of atherosclerosis continues to be lowering of serum LDL-C. In this regard, the statins have...

Role of nitric oxide in the angiogenic process

Convincing in vivo evidence that endothelial factors play a major role in mediating the angiogenic response was found in murine studies of apoE-hypercholesterolemic mice. These mice exhibit attenuated collateral vessel formation in response to a FGF-2 disk angiogenesis system in a hind-limb ischemia model (81,128). This inhibition was fully reversed by the oral administration of l-arginine, which is the substrate for endothelial NO production. In a porcine model of chronic myocardial ischemia, evidence was recently produced that hypercholesterolemia-

Properties of the Coronary Microcirculation

Arginine for eNOS, asymmetric dimethylarginine. Abnormalities of G protein signaling, resulting in reduced activation of eNOS in response to endothelial cell receptor activation, have also been shown to occur. A substantial body of data suggests that in some of these conditions (hypercholesterolemia, hypertension, and diabetes), increased production of vascular superoxide (*02-) occurs. Superoxide reacts very rapidly with NO*, leading to the formation of the toxic peroxynitrite anion. Although peroxynitrite can produce vasodilation, it is a very weak vasodilator, and as a result this reaction significantly reduces the amount of bio-available No. The initial studies demonstrating abnormal endothelium-dependent vascular relaxation in various disease models were performed in larger vessels. Subsequent experiments have shown that most, if not all, of these disease processes also affect the coronary microcirculation in a similar fashion. This is of particular interest in the case of...

Glucagon receptor antagonists

That promote glycogen breakdown as well as its storage. The three isoforms of GP, brain, liver and muscle share about 80 homology. Inhibition of liver GP in T2D is considered to be desirable in view of its rate-limiting role in glycogenolysis and indirect inhibitory role in gluconeogenesis pathways. The activity of GP is known to be modulated by the affinity of ligands binding to six different binding sites, thus offering multiple opportunities for its modulation. The most interesting of these is the allosteric site which spans the GP dimer interface characterized by the identification of the inhibitor CP-320626, 32 43 . Compound 32 was found to be efficacious at 10mg kg po dose in ob ob mice 44 . A compound from this class has been studied clinically, and preliminary results have confirmed its glucose lowering potential 45 . Related compounds have recently been shown to reduce cholesterol in several species through inhibition of lanosterol demethylase 46 . Other inhibitors of GP...

Acute microvascular effects of growth factors

B High-cholesterol diet B High-cholesterol diet Fig. 7. Microvascular reactivity studies after 4 wk of vascular endothelial growth factor (VEGF) treatment in a porcine model of myocardial ischemia with (B,C) or without (A) hypercholesterolemia-induced endothelial dysfunction. Graphs show percent relaxation to increasing concentrations of vasodilating agents following preconstriction with U46619. SNP, sodium nitroprusside ADP, adenosine diphosphate. From ref. 146. Fig. 7. Microvascular reactivity studies after 4 wk of vascular endothelial growth factor (VEGF) treatment in a porcine model of myocardial ischemia with (B,C) or without (A) hypercholesterolemia-induced endothelial dysfunction. Graphs show percent relaxation to increasing concentrations of vasodilating agents following preconstriction with U46619. SNP, sodium nitroprusside ADP, adenosine diphosphate. From ref. 146. Fig. 8. Post- vs prevascular endothelial growth factor (VEGF) treatment ratios of ischemic (left circumflex...

Combination Antioxidant Secondary Prevention Trials

Trials testing combinations of antioxidants in secondary prevention are summarized in Table 3.7. The HDL-Atherosclerosis Treatment Study (HATS) was a trial of 160 patients with CHD, normal LDL cholesterol, and low HDL cholesterol who were randomized to a relatively high-dose combination of four antioxidants (800IU of vitamin E, 1,000mg of vitamin C, 25 mg of beta-carotene, and 100 g of selenium) and or lipid-modifying therapy (simvastatin to lower LDL and niacin to raise HDL) vs. placebo.64 After 3 years, simvastatin niacin therapy decreased both coronary stenosis (P 0.004 vs. placebo) and the event rate for a combined endpoint of death from coronary causes, MI, stroke, or revascularization (3 vs. 24 for placebo, P 0.03). The antioxidant-only group did not show a reduction in coronary stenosis (P 0.16 vs. placebo) or CVD events. While supplemental antioxidants attenuated the angiographic benefits of lipid-modifying therapy (P for interaction 0.02) and diminished the clinical benefits...

Morphological and functional characterization of bm adipocytes

Histochemically, BM adipocytes essentially contain neutral triglycerides and free fatty acids, most of which are saturated and monounsaturated (52). Bone marrow adipocytes thus stain well with Oil red O and Nile blue sulfate. The cytochemical staining pattern of freshly isolated marrow and extramedullary adipocytes (54) reveals differences in esterase activity (Table 1).

Pharmacology of the coronary microcirculation

3-Hydroxy-3methylglutaryl (HMG)-coenzyme A reductase inhibitors (or statins) also exert direct beneficial effects on the endothelium, in part through an increase in NO production (170). They can promote angiogenesis independently of direct changes in eNOS expression, but rather by stabilization of eNOS mRNA (171), and modulation of hsp90 and caveolin abundance, contributing to eNOS availability and functionality to potentiate the NO-dependent, protein kinase AKT-activated angiogenic process (172,173). Although these pro-angiogenic properties can be observed at low doses, statins could paradoxically exert anti-angiogenic effects at high dose (174), in association with decreased endothelial release of VEGF, increased endothelial apoptosis (175), and of Rho A geranylgeranylation and membrane localization (176).

Cigarette Smoking And The Risk Of Stroke

Heavy smoking ( 20 cigarettes day) increases both the incidence 37-41 and mortality from stroke 40,41 , Cigarette smoking is a major modifiable risk factor for subarachnoid hemorrhage 42-48 , In contrast, evidence concerning the role of tobacco in the risk of intracerebral hemorrhage is still controversial, yet it appears that heavy, but not light-to-moderate cigarette smoking, increases the risk 9,38,49,50 , Smoking is dose-dependantly associated with the risk of ischemic stroke 38,46 , Cessation of smoking reduces stroke risk 37,39 , with major reduction within 2-5 years after cessation 37,39,46 , indicating that part of the effects of smoking is reversible. The risk of stroke seems to return to the level of never-smokers in light smokers, but heavy smokers seem to retain an increased risk even though also they benefit from cessation 37 , There are several mechanisms by which smoking may cause stroke. Cigarette smoking causes an immediate, yet reversible increases in blood pressure...

Carotid Atherosclerosis Arterial Stiffness and Stroke Events

Assessment of intima-media thickness or of measures of large arteries compliance may identify patients at increased risk for stroke. In fact, carotid atherosclerosis and arterial stiffness are both related to risk factors associated with the occurrence of stroke. In addition, several cross-sectional studies have shown that risk factors associated with the occurrence of stroke have been correlated with carotid atherosclerosis development and progression and with increased arterial stiffness. Some studies have also shown that aortic stiffness is associated with the extent of atherosclerosis in the carotid and in other vascular beds. More importantly, longitudinal studies have demonstrated that carotid atherosclerosis and arterial stiffness are independent predictors of stroke (and other cardiovascular events). Interventional studies have demonstrated that treatment with statins, calcium antagonists, ACE inhibitors, and insulin sensitizers may be particularly effective on slowing the...

The Effect Modification Of Alcohol By Smoking

There are only two epidemiologic studies on the effect modification of alcohol by smoking and neither of them examines it in relation to the risk of stroke. In a Japanese cohort of 19,231 men, alcohol consumption and all-cause mortality had a J-shaped association in nonsmokers but not in smokers 78 , In a cross-sectional study of 5,312 German men and women, the rise in blood pressure associated with drinking was higher in smokers than in nonsmokers 79 , Some studies have instead examined the effect modification of smoking by alcohol. In a cohort of 22,071 US male physicians, alcohol attenuated the linear effect of smoking on the risk of total stroke 38 , In a Japanese cohort of 1,775 men, a dose-dependent decrease in diastolic blood pressure and serum HDL cholesterol by increasing cigarette smoking was evident in nondrinkers but not in drinkers The effects of both alcohol and tobacco are manifold, which makes them complicated to examine and understand. The effects may be additive or...

Alternative delivery modalities

Tissue engineering has also emerged as a feasible method for facilitated angiogenesis and or myogenesis, with myocardial transplant of myoblast-derived bioartifical muscles (BAMs) or three-dimensional fibroblast scaffolds as epicardial patches, increasing vascular growth up to threefold (178-180). Finally, angiogenic and myogenic processes may be augmented through mobilization of endogenous cells that may have intrinsic tropism for and biological activity within areas of cardiac injury. Toward this end, recent studies have examined ischemic injury alone, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), VEGF, statins, and many other biological products for progenitor cell mobilization (15,181185). The efficacy of these methods in promoting cardiac angiogenesis and or myogenesis has yet to be fully established.

Epidemiological Studies

Recently, the South Bay Heart Watch (Torrance, CA) reported a study ofl,196 asymptomatic subjects with coronary risk factors who were assessed for alcohol consumption history and for the presence of calcium deposits in coronary atherosclerotic lesions as measured by electron beam computed tomography (EBCT). Participants were followed prospectively for 41 months for coronary events, defined as the occurrence of myocardial infarction or CHD death 6 , Subjects who drank alcohol had a relative risk of 0.3 ofhaving a coronary event compared with abstainers. The diminished risk of myocardial infarction or CHD death associated with moderate alcohol consumption was independent of serum HDL cholesterol levels, EBCT coronary calcium scores, and all other coronary risk factors. Abstention from alcohol in this study was as strong a predictor of coronary events as diabetes, smoking, hypertension, and coronary calcification 6 , Also reported recently was an analysis of the relationship between...

Management options

Treatment with cholestyramine, antihistamines or topical preparations has variable success. Corticosteroids have also been used, but most women are now treated with ursodeoxycholic acid, which has been shown to improve symptoms and reduce serum bile acid levels. Both the mother and the neonate should receive vitamin K therapy.

Clinical Box 32 Inhibitors of Cholesterol Biosynthesis

It is estimated that approximately 30 of the population in the United States has circulating cholesterol levels that exceed desirable levels ( 200 mg dL) (American Heart Association). Elevated cholesterol levels are a major indicator for the development of coronary artery disease and a number of factors contribute to the high prevalence of excess circulating cholesterol, including genetic disposition and lifestyle issues. While familial hypercholes-terolemia is one of the most common genetic diseases in the United States (prevalence between 1 500 and 1 700), it accounts for only a small fraction of patients with elevated cholesterol. Changes in diet and exercise among patients diagnosed with elevated cholesterol levels can lead to a reduction in circulating cholesterol levels for about 10 of the population. These simple changes work because circulating cholesterol levels arise from two distinct sources from our diet and direct synthesis by the body. If we take in less cholesterol in...

Oxidized Lipoproteins

Pharmacological Agents - Probucol (1), a lipid lowering drug, can also act as an antioxidant to protect LDL against Cu++-mediated oxidation (70,71). Prevention of the progression of atherosclerosis in WHHL rabbits has also been reported independently by two groups (71,72). Since probucol did not prevent foam cell formation of macrophages of WHHL rabbits or mice directly, it was concluded that the antiatherosclerotic effect of this drug in WHHL rabbits was mainly due to its inhibitory effect on the oxidation of LDL (73). However, no effect of probucol treatment on the formation of atheroma was seen in cholesterol-fed rabbits kept at comparable plasma cholesterol levels (74). Other hindered phenols and analogs were also tested with regard to their hypolipidemic and

Cigarette Smoking And Cardiovascular Disease

Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms of their effects on cardiovascular system were not totally clear. The effects of nicotine and carbon monoxide on blood vessel walls, unfavorable lipid profiles, increased myocardial work and the decreased oxygen carrying capacity of the blood of smokers contribute to the overall effect of cigarette smoking on cardiovascular disease 3J. Of the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth of this is due to smoking-induced changes in serum lipid 4 , The majority of studies indicate elevations in serum cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in smokers, with decreased serum high-density lipoprotein (HDL) cholesterol 5 , A mechanism to explain the link between smoking and some of the observed changes in serum lipid and lipoprotein concentrations includes the...

Peripheral Biomarkers

Fluxes, abnormal glutamate transporter activity, decreased phospholipase A, decreased phospholipase C activity, and increased cytosolic protein kinase C levels 100-104 . Moreover, a number of laboratories independently described alterations in APP metabolism concentration in platelets of DAT patients when compared with control subjects matched for demographic characteristics 105-107 . In particular, two research groups have reported that AD is associated with a decrease in the amount of the higher (130-kDa) band compared with the lower (110-kDa) band 108, 109 . Reduction in the APP isoform ratio was found to be correlated with disease severity and progression 110, 111 . Sensitivity and specificity for AD diagnosis was in the 80 -95 range, based on post hoc cutoff scores 109 . A significant reduction was also observed in a sample fulfilling criteria for MCI, particularly in those MCI subjects who progressed to DAT 2 years later. In fact, sensitivity and specificity for prediction of...

The Coeffect Of Alcohol And Tobacco Smoking

Numerous studies have indicated a correlation between ethanol intake and cigarette smoking in heavy drinkers 30 , On a pharmacological basis, an ethanol-induced potentiation of nicotinic currents may enhance the acute positive reinforcement associated with nicotine, increasing tobacco use during heavy ethanol intake. Ethanol may enhance acute nicotine-mediated receptor activation. Moreover, the opposing effect of ethanol on nicotine-induced desensitization could account for the increased tobacco use observed with excessive drinking. The dose relationship between the combined use of these two social habits and the changes in serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides, has been investigated 31 . Both social habits raised serum cholesterol levels in a dose-related manner the more cigarettes a subject smokes and the more alcohol consumed, the higher the total serum cholesterol 31 ,

Lipodystrophy in hivinfected subjects

Patients with LDHIV often have dyslipidemia, insulin resistance, and hepatic steatosis. Dyslipidemia in the form of hypertriglyceridemia, hypercholesterolemia, and low HDL cholesterol is much more common (50-70 ) than hyperglycemia (0-20 ) (55,56). Metabolic abnormalities may sometimes precede changes in body fat distribution.

Mechanistic Multiplicity Of Statin Effects

This mevalonate pathway is important not only for cholesterol biosynthesis but also for the formation of the isoprenoids and their precursors, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), both of which are involved in regulatory post-translational isoprenylation of proteins involved in many signal transduction pathways. For example, Ras is farnesylated at the C terminal CAAX box, whereas the Rho family members of small molecular weight GTPases, including Rho, Rac and cdc42, are modified by geranylgeranyl transferase. These proteins are key intracellular signalling molecules that play a pivotal role in regulating cellular activities such as cell polarity, intracellular vesicle trafficking, progression through cell cycle, differentiation, gene transcription, cell migration (chemotaxis) 7-9 . Isoprenylation of proteins alters subcellular localization and facilitates their association with membranes and downstream effectors such as the actin cytoskeleton and p160...

Inhibitors Of Hepatic Glucose Production

Thiazolidinediones (TZDs) - The mode of action and clinical benefits of the TZDs have been recently reviewed (40). Evidence is mounting that the PPARy receptor is the target of the TZDs (41). Idiosyncratic liver dysfunction has been observed in 2 of patients in early troglitazone (Rezulin) trials which has caused market restrictions in Europe and the US (42-45). Pioglitazone (17, Actos) and rosiglitazone (18, Avandia) were both launched in the US in 1999. Pioglitazone in doses of 30 mg and 45 mg resulted in reductions in mean HbAic of 2.3 and 2.6 from baseline in previously untreated patients (46,47). Rosiglitazone given 4 mg bid results in a 1.5 reduction in HbAic relative to placebo, and reduces HbAic 1.2 over metformin alone (48-50). Englitazone 19 may have an effect on gluconeogenesis in Zucker rat livers and has been used to probe the insulin signaling pathway in vitro (51,52). Darglitazone 20 has been shown to increase body weight in fatty Zucker rats due to increased feeding...

Targeting Nonhepatic Hmgcoa Reductase

Statins are now widely used in clinical practice and have proven to be well-tolerated and safe. As detailed above, the widespread use of statins has led to observations of anecdotal benefit unrelated to their inhibition of hepatic HMG-CoA reductase. The principal adverse effects are recognised to be liver and muscle toxicity 137 . Elevated hepatic transaminase has been observed in 0.5-2 of cases and is dose-dependent being reversible with a reduction in dose. Myopathy is recognised to be the major significant adverse effect for statins. This is frequently a non-specific, mild myalgia comprising muscle aches and cramps without elevation of creatine kinase. Rarely, statin treatment can lead to a myositis with muscle soreness and weakness associated with an elevated creatine kinase. This can lead to rhadomyolysis with myoglobinuria and acute renal necrosis. This side effect, although very rare, resulted in the voluntary withdrawal of cerivastatin in 2001. Understanding the mechanism of...

Lipids And Cardiovascular Disease

And lesions and are related to the course of myocardial infarction 116,122 . However, atherosclerotic plaque formation and the mechanisms for the ensuing increased morbidity and mortality are complex processes, which involve, for example, the production of superoxide by monocytes, and the formation of autoantibodies against oxidized LDL and MDA-LDL 123,124 , In aortic muscle or endothelial cells in vitro, oxidized LDL can increase collagen and fibronectin synthesis, apoptosis, intracellular calcium and TBA formation 122,125 , Moreover, concomitant pathologies such as hypertension are additional risk factors for the etiology of atherosclerosis. For example, in hypertension, ATC status as reflected by red blood cell (but not plasma), concentrations is lower than that of normotensive controls 126 , Age-related reductions in the anti-oxidant capacity of plasma, acting against peroxyl radicals, may also contribute to the atherosclerosis 127 , There is also a tentative association between...

Rafts As Potential Targets Of Therapies

The cholesterol reducing drugs, the statins, already in widespread use in the clinics have been shown to modulate T cell responses (73). It is possible that drugs that effect membrane cholesterol levels and consequently raft functions could be effective immunosuppressants.

Obesity And Abdominal Adiposity

Prospective study of over 1 million adults in the US evaluated the relationship between BMI and cardiovascular mortality as well as all-cause mortality20. The risk of death from cardiovascular disease as well as all causes was noted to increase progressively over the range of overweight to clinically obese patients regardless of age or sex (Figure 7.7)20. One study demonstrated that risk factors for coronary artery disease such as low HDL cholesterol levels, systolic blood pressure, triglycerides, glucose, and serum total cholesterol often cluster with obesity21. The study also demonstrated that a 2.25 kg weight reduction was associated with a 48 reduction in the sum of risk factors for coronary artery disease in man and a similar 40 reduction in women21. A recent study investigated the relationship between being overweight or obese at 40 years of age and life expectancy22. Overweight and obesity were both strongly associated with

Blood Lipids and Coronary Heart Disease

The major risk factors for coronary heart disease are well known and include smoking, high blood pressure, and blood cholesterol levels. In addition, obesity, diabetes, and family history are recognized as important factors. While each of these factors is important, the predominant factor may be blood cholesterol levels. Serum total cholesterol and lipoproteins are well-established risk factors for coronary artery disease. Numerous studies have confirmed the relationship between serum total cholesterol and coronary heart disease.1013 A rule of thumb from epidemiologic studies suggest that for every 1 increase in total cholesterol, the risk of CHD increases by 2 .14,15 The National Cholesterol Education Program defines three categories of serum total cholesterol. These are desirable (240 mg dL). These classifications have been used as a basis for prescribing preventive treatments including dietary changes and pharmaceutical drugs.14 NCEP guidelines have changed with the development of...

Impact of Lipid Reduction on Arterial Stiffness

In animal models of hypercholesterolaemia, cholesterol-lowering appears to reduce arterial stiffness 14, 15 . In man, a number of studies have addressed the effect of HMG-CoA reductase inhibitors (statins) on large artery stiffness (table 3). Kool et al. 32 failed to find any impact of pravastatin on carotid,

Clinical Considerations From The Epidemiological Data

Several decades, and only In later stages do noticeable clinical signs appear. Using amyloid pathology as an example, the earliest detectable events appear to be release of Ap peptide from neurons. This process, which often starts in the sixth or seventh decade of life, can remain largely asymptomatic until the eighth or ninth decade of life. In the early stages, diffuse extracellular Ap deposits form that have little obvious deleterious effect on the surrounding brain tissue (63, 64). The appearance of the dense-core neuritic plaques, usually many years later, temporally corresponds more closely to the onset of clinical symptoms. So, for example, a treatment that blocks the generation and release of Ap from neurons may show good efficacy if chronically administered in the pre-symptomatic stages of AD when Ap is first being released from neurons, but have little effect once symptoms begin and massive extracellular deposits of Ap already exist. The use of statins in treating...

Mechanisms Linking Stiffness and Cholesterol

Cholesterol and oxidized LDL cholesterol, in particular, have a number of direct, non-atheromatous, effects on the arterial wall, which may lead to arterial stiffening. Oxidized LDL cholesterol also leads to peroxynitrite formation and a generalized state of increased oxidative stress, both of which can damage elastin directly 37, 38 . Oxidized LDL cholesterol is also pro-inflammatory. Several groups, including our own, have recently shown an association between measures of acute inflammation, such as C-reactive protein and arterial stiffness in otherwise healthy individuals 39, 40 . Moreover, Pirro et al. recently found a significant, positive relationship between aortic pulse wave velocity and C-reactive protein in subjects with hypercholesterolaemia. Interestingly, when both C-reactive protein and HDL cholesterol were entered into a multivariate model, only C-reactive protein remained an independent predictor of aortic stiffness. Hypercholesterolaemia is strongly associated with...

Preclinical models of therapeutic angiogenesis in peripheral arterial disease

Less complete endogenous angiogenic response to ischemia have been developed. Arterial ligation followed by complete excision of the femoral artery produces an ischemic normal limb flow ratio and a blunted angiogenic response that more closely mimics PAD, and intermittent claudication in particular (28,29). Subsequent administration of angiogenic growth factors or angiogenic gene therapy leads to more rapid and complete recovery, as manifested by enhanced collateral vessel development, increased capillary density, and improved calf blood pressure ratios (25-27,30-39,51). When arterial ligation and excision is applied to animal models with hypercholesterolemia, diabetes or hyperhomo-cystemia, an even more profound impairment in the endogenous angio-genic response, results, and this scenario is more analogous to critical limb ischemia (40-44). Therapeutic angiogenesis in this setting will seek to prevent limb loss (40-44). All of the angiogenic growth factors that have entered human...

Flavorcontributing Microorganisms

The mold responsible for the well-known blue-veined appearance of Roquefort, Gorgonzola, and other blue cheese types is P. roqueforti. Although spores of P. roqueforti are added to milk or curds before the lactic fermentation, mold growth does not occur until after the lactic culture has fermented all or most of the available lactose to lactic acid. Lactic acid serves as an energy source for the mold. Importantly, consumption of lactic acid causes the pH to rise from about 4.6 to as high as 6.2 (Marth and Yousef, 1991). As P. roqueforti grows in cheese, substantial proteolysis occurs through elaboration of several extracellular protein-ases, endopeptidases, and exopeptidases. Amino acids can be subsequently metabolized releasing amines, ammonia, and other possible flavor compounds (that also may raise the pH). However, the most characteristic blue cheese flavors are generated from lipid metabolism (Gripon, 1987). As much as 20 of triglycerides in milk are hydrolyzed by lipases...

Mitochondria Oxidative Stress and Bioactive Lipids A New Concept

In this regard, an important aspect of mitochondrial metabolism is the concept that a threshold effect exists, wherein the bioenergetic function of mitochondria is compromised following the attainment of mitochondrial DNA damage at a particular threshold level. Beyond this threshold level, mitochondria cannot produce sufficient energy for the cell and there is an increase in reactive oxygen species. This causes extensive damage of surrounding cells, lipid peroxidation, and further elevation above the threshold levels. Mitochondrial DNA encodes 13 proteins which have important roles in the respiratory chain. Maintenance of bioenergetic capacity is dependent on the synthesis of these proteins. As the level of mitochondrial DNA damage increases, the likelihood of dysfunction also increases. When the threshold for DNA damage is reached, there is low synthesis of the critical proteins and a low bioenergetic capacity, relative to needs. Mitochondrial DNA damage is associated with several of...

Proteincoated artificial cells in immunoadsorption

Albumin can bind tightly to the ultrathin collodion membrane of adsorbent artificial cells, and was initially used to increase the blood compatibility of the adsorbent artificial cells for hemoperfusion (Chang, 1969a). This albumin coating has also been applied to synthetic immunosorbents, resulting in blood compatible synthetic blood group immunosorbents (Chang, 1980d). The albumin-coated synthetic adsorbent has been applied clinically for removing blood group antibodies from plasma for bone marrow transplantation (Bensinger et al., 1981). In addition, albumin-coated collodion activated charcoal (ACAC) was found to effectively remove antibodies to albumin in animal studies (Terman et al., 1977). This principle has become a basis of one line of research in which other types of antigens or antibodies are applied to the collodion coating of the activated charcoal to form immunosorbents. Other immonosorbents based on the same principle have also been developed for the treatment of human...

Selectivity And Polypharmacology

Inhibitors of HMG-CoA reductase and angiotensin I-converting enzyme (ACE) give examples of multiple indications deriving from modulation of one primary target. The myriad of pleiotropic effects of statins has been proposed to be dependent upon their effect on depletion of sphingolipid rafts and thus a reduction in the cell surface expression of many important immuno-signaling receptors caused by reduction in cellular production of cholesterol, by their primary mode-of-action the inhibition of HMG-CoA reductase 61 . Likewise the beneficial effects of ACE inhibitors have been proposed to be due to the position of ACE at the rate-limiting nexus of multiple disease pathways. Epidemiologic results from genetic association studies and clinical outcomes experience indicate that of over-activity of ACE may underlie several age-related diseases 62,63 . they exhibit poly-pharmacology 64 . Arguably the initial and extremely successful drug discovery strategy employed by Paul Janssen can be...

Adipokines and Steatosis

Our understanding of the role of resistin in the development of steatosis is quite preliminary. Resistin is capable of influencing lipid metabolism in rodents. Resistin overexpression in mice and rats leads to plasma TG increases and to significant dyslipidemia (81). Serum resistin levels correlate negatively with HDL cholesterol levels in healthy men (82), suggesting that higher-than-normal resistin levels typically seen in obesity and type 2 diabetes might contribute to the development of fatty liver through its dyslipidemic effects.

Genetic Risk Factor for Alzheimer Disease

Linkage between AD and 19q13.2 was observed in a group of families with late-onset AD. Because the gene (APOE) for apolipoprotein E is in this region, it became a candidate for familial late-onset AD. The APOE gene is polymorphic for three common alleles, APOE*2, APOE*3, and APOE*4, that occur in most populations with frequencies of about 8 , 78 , and 14 , respectively. Each APOE allele encodes a distinctive isoform ApoE2, ApoE3, and ApoE4. Apolipoprotein is synthesized primarily in the brain by astrocytes. Among other functions, apolipoprotein E sequesters cholesterol and triglycerides from cellular debris and transports these molecules into neurons, where they are used for the formation of synaptic membranes.

Human and nonhuman primate studies

Apolipoprotein A-I is the most abundant protein in HDL and plays an important role in maintaining the structure of HDL and activating lecithin cholesterol acyltransferase (LCAT), an enzyme involved in converting cholesterol to cholesterol ester. HDL appears to be primarily cardioprotective by transporting cholesterol from the periphery to the liver for export as bile acids. This process is termed reverse cholesterol transport. From epidemiological studies, higher levels of HDL cholesterol are associated with a decrease in cardiovascular disease risk. Similar studies have shown that apolipoprotein A-I levels show a similar inverse relationship with risk for cardiovascular disease 4 , Consumption of moderate amounts of alcohol is associated with an increase in HDL cholesterol and apolipoprotein A-I. The increases occur in a dose-dependent fashion. As little asl5gof alcohol day can increase apolipoprotein A-I levels in humans 5 , Hojnacki et al. 6 examined the dose response of alcohol on...

Assessment of overweight and obesity in epidemiological studies of disease

Many studies have found moderate to strong correlations (r 0.6 to 0.9) between BMI and densitometry estimates of body fat composition in adult populations (5). The validity of BMI as a measure of adiposity is further supported by its association with obesity-related risk factors such as blood triglycerides, total cholesterol, blood pressure,

Plasma membrane cholesterol and lipid rafts

Recent studies have identified differences in plasma membrane cholesterol levels between transitional and mature B lymphocytes. Furthermore, studies in which cholesterol levels were augmented in transitional B lymphocytes to levels comparable to those in mature B lymphocytes suggest that these differences are responsible for both the differential ability to stably organize BCR into lipid rafts and relative ability to maintain signaling pathways associated with PI-hydrolysis and PKCp activation (Karnell et al., 2005 Monroe, 2005). The mechanisms regulating the developmental difference in cholesterol levels are unknown but could reflect variations in cholesterol uptake and or biosynthesis by B lymphocytes. The implications of these results are profound, for they indicate that developmental-related differences in plasma membrane cholesterol levels affect the ability to organize lipid rafts and point to potential risk factors for B lymphocyte autoimmune diseases. For example, genetic or...

The Metabolic Syndrome

And in women 35 inches ( 88 cm)) Elevated triglycerides (a 150 mg dL) Low HDL cholesterol (men 40 mg dL and women 50 mg dL) High blood pressure (a 130 85 mmHg) Impaired fasting glucose (a 110 mg dL) syndrome occur together with great frequency. Several definitions of the metabolic syndrome exist including ones from the NCEP ATP III, the WHO, and the International Diabetes Federation. In general, most definitions endorse the following basic criteria a measure of abdominal adiposity, hypertriglyceridemia, low HDL cholesterol levels, hypertension, and evidence of impaired glucose metabolism. The NCEP ATP III defines the metabolic syndrome as any three of the following elevated triglycerides (a 150 mg dL), low HDL cholesterol (men 102 cm, and women 35 inches, or 88 cm) (Table 7.5)33. The prevalence of the metabolic syndrome has steadily increased especially among middle-aged adults in the US, in part because of increasing clinician comfort with diagnosis, but also secondary to increasing...

Apolipoproteins CII and CIII

Apolipoproteins C-II and C-III both play a major role in VLDL metabolism. Apolipoprotein C-II and C-III stimulate and inhibit, respectively, lipoprotein lipase, the enzyme responsible for hydrolyzing the triglycerides in VLDL. In one study comparing apolipoprotein E levels among low (50 g day) and alcoholic ( 100 g day) drinkers showed a significant increase in serum apolipoprotein C-III levels with increasing alcohol consumption 43 , Incubating human hepatoma cells with alcohol with concentrations up to 50 mM had no effect on apolipoprotein C-II or apolipoprotein C-III secretion 43 ,

Dimensions Of Regions Of The Gastrointestinal Tract

Figure 2 Diagram of a typical intestinal epithelial cell (enterocyte). Enterocytes are high cuboidal to low columnar epithelial cells that rest on a basement membrane. Enterocytes are joined firmly to adjacent cells by tight junctions. The nucleus resides in the basal portion of the cell. The apical surface of the cell exhibits numerous microscopic projections (microvilli) that give the appearance of a brush border'' when seen with a light microscope. Microvilli greatly increase the available absorptive surface area for the enterocyte. Nearly all substances taken up from the intestinal lumen must traverse the cytoplasm of an enterocyte. Lipids and fats are absorbed at the base of the microvilli, traverse the enterocyte cytoplasm, and exit the enterocyte at its side, beneath the tight junctions. In contrast, amino acids, triglycerides, and carbohydrates are absorbed along the length of the microvilli, traverse the enterocyte cytoplasm, and exit the cell at its base. Reproduced from...

Primary Thromboprophilaxis in aPLPositive Patients

Thus, low-dose aspirin (75 mg day) is considered as a logical prophylaxis in individuals with persistently positive aPL and or unequivocally positive LA tests in case of aspirin allergy or intolerance, other antiaggregant drugs should be considered. Prothrombotic factors should be avoided (i.e., smoking, estrogen-containing oral contraceptive pills) and or treated (i.e., hypertension, hypercholesterolemia, diabetes mellitus) in all patients. Furthermore, high-risk situations (such as surgery, long-haul travel) should be covered with subcutaneous heparin prophylaxis.

Other Side Effects of ATRA

Dryness of lips and mucosae are usual but are reversible with symptomatic treatment. Increases in transaminases and triglycerides are common, but they have never required treatment discontinuation in our experience. Headache, due to intracranial hypertension, is generally moderate in adults but may be severe in children, and associated with signs of pseudotumor cerebri 46 . Lower ATRA doses (25 mg m2 per day) reduce this side effect in children and seem as effective as conventional doses of 45 mg m2 per day in inducing CR 46 . Isolated fever frequently develops in the absence of other signs of ATRA syndrome (or infection) and is reversible within 48 h of ATRA discontinuation 37,109 .

In the cardiovascular system

Much evidence has accumulated from various lines of inquiry that indicates that the dietary fatty acid intake and lipid acyl composition of tissues is a determinant of many of the chronic diseases prominent in the Western World, notably cardiovascular disease. It has been appreciated since the 1950s that when dietary polyunsaturated fat intake is increased, a decrease in the total serum and lipoprotein cholesterol levels results 1 . Bang and Dyerberg, in their study of the Greenland Eskimos, a group in which CVD had an extremely low incidence, made the ground breaking inference that the high dietary intake of the long chain polyunsaturated fatty acids, eicosapentanoate and docosahexaenoate was responsible for this protection from disease 2 , More recently, several epidemiological studies have reported a relationship between dietary n-3 polyunsaturates and the risk of CVD 3-8 , For example, Dolechek et al. found an inverse relationship between alpha-linolenate and mortality from CVD,...

Protein coated artificial cells in immunoadsorption

Albumin can bind tightly to the ultrathin collodion membrane of adsorbent artificial cells (Chang, 1969a). This was initially used to increase the blood compatibility of the adsorbent artificial cells for hemoperfusion (Chang, 1969a). We also applied this albumin coating to synthetic immunosorbents resulting in blood compatible synthetic blood group immunosorbents (Chang, 1980d).This albumin-coated synthetic adsorbent has been applied clinically for removing blood group antibodies from plasma for bone marrow transplantation (Bensinger et al., 1981). In addition, albumin-coated collodion activated charcoal (ACAC) was found to effectively remove antibodies to albumin in animal studies (Terman et al., 1977). This has become the basis of one line of research in which other types of antigens or antibodies are applied to the collodion coating of the activated charcoal to form immunosorbents. Other immonosorbents based on this principle have also been developed for the treatment of human...

Class II the Metabolic Sensors

The LXRs are master regulators of cholesterol homeostasis, effecting cholesterol conversion into bile acids and direct export from the liver into bile acids, as well as cholesterol efflux in peripheral tissues.136 172 Oxysterols, metabolites of cholesterol, act as LXR ligands, activating LXR when intracellular cholesterol levels are high.75,97 The LXR response element (LXRE) is a direct repeat separated by four nucleotides (DR-4). There are two forms of LXR alpha and beta. LXRalpha is predominantly expressed in the liver, adipose tissue, and macrophages, while LXRbeta is ubiquitously expressed.141 When challenged with a cholesterol rich diet, LXRalpha knockout mice accumulate cholesterol esters in their liver and have an increased rate of plaque formation.136,169 The LXRbeta knockout mice have a normal phonotype indicating that LXRalpha is the dominant player in the liver.1 LXRalpha and LXRbeta macrophage specific double knockout, developed by bone marrow transplantation, displays...

Surface Properties of Artificial Cell Membranes

Albumin can bind tightly to the ultrathin collodion membrane of adsorbent artificial cells. This is initially used to increase the blood compatibility of the adsorbent artificial cells for hemoperfusion (Chang, 1969a). This albumin coating has also been applied to synthetic immunosorbents, resulting in blood compatible synthetic blood group immunosorbents (Chang, 1980d). In addition, Terman etal. (1977) showed in animal studies that albumin-coated collodion activated charcoal (ACAC) can remove antibodies to albumin. This has become a basis of one line of his research in which other types of antigens or antibodies are applied to the collodion coating of the artificial cells to form immunosorbents. Other immunosorbents based on this principle have also been developed for the treatment of human systemic lupus erythematosus removal of antiHLA antibodies in transplant candidates treatment of familial hypercholesterolemia with monoclonal antibodies to low-density lipoproteins (Terman, 1980

CVD Risk Associated With Obesity

The association between overweight obesity and CVD risk has been known for many years with evidence from several large cohort studies (74-76). After 44 yr of follow-up of the Framingham Heart Study, Wilson et al. (77) showed that CVD risk (including angina, myocardial infarction, CHD, or stroke) was higher among overweight men (RR 1.24 95 CI 1.07-1.44), obese men (RR 1.38 95 CI 1.12-1.69), and obese women (RR 1.38 95 CI 1.14-1.68) after adjustment for age, smoking, high blood pressure, high cholesterol, and diabetes. During a 14-yr follow-up of 1 million adults in the United States, it was found that as BMI increased there was an increase in the risk of death from all causes, CVD, cancer, or other diseases for both men and women in all age groups (78). These findings confirmed the previous report of the Nurses' Health Study (79). In the Nurses' Health Study, weight gain of 5 to 8 kg increased CHD risk (nonfatal myocardial infarction and CHD death) by 25 , and weight gain of 20 kg...

Atherosclerosis and Coronary Artery Disease

A cross-sectional study by Takami et al. (88) of 849 Japanese men aged 20 to 78 yr investigated the relationship between body fatness (particularly abdominal fat) and carotid atherosclerosis. They found that general adiposity (as measured by BMI), WC, waist-to-hip ratio (WHR), abdominal subcutaneous fat, and intra-abdominal fat were all correlated with carotid IMT after adjustment for age and smoking habits. Adjustment for BMI eliminated all other associations except those of WHR with IMT, suggesting that in this population abdominal fat is not as strongly associated with carotid atherosclerosis as is general body fatness. The Progetto ATENA study is a large (more than 5000 participants) ongoing investigation of the causes of CVD and cancer in Italian females aged 30 to 69 yr. Within that study, De Michele et al. (89) reported on a sub-sample of 310 women and concluded that BMI and WHR were significant predictors of carotid wall thickness independent of other cardiovascular risk...

Type 2 Diabetes Mellitus

In addition, it has been demonstrated in the Framingham Offspring Cohort that metabolic factors associated with obesity (overall and central), including hypertension, low levels of HDL cholesterol, and increased levels of TG and insulin, worsen continuously across the spectrum of glucose tolerance (111). Although BMI increased steadily with increasing glucose intolerance, the association between most other measures of metabolic risk and glycemia were independent of overall obesity, and the gradient of increasing risk was similar for nonobese and obese participants (111). Thus, asymptomatic glucose intolerance is not a benign metabolic condition, and characteristics associated with insulin resistance syndrome should be taken seriously. This is further reinforced by the Quebec Cardiovascular Study, where hyperinsulinemia was reported as an independent risk factor for CHD (112).

Long Term Health Consequences of PCOS

Insulin resistance is associated with diabetes, hypertension, dyslipidemia, endothelial dysfunction, a procoagulant state, and cardiovascular disease (see Chapters 28 and 29). Recently, the National Cholesterol Education Program Adult Treatment Panel defined the metabolic syndrome as the presence of three of the five following risk factors waist circumference greater than 88 cm in females fasting serum glucose 110 mg dL or more, fasting serum triglycerides greater than 150 mg dL serum high-density lipoprotein cholesterol less than 50 mg dL and blood pressure greater than 130 85 mmHg (60). The metabolic syndrome has been found to be present in 43-46 of women with PCOS, a twofold higher prevalence compared with women in the general population of the same age (61,62).

Exercise and weight loss

HDL cholesterol (mg dL) Total HDL cholesterol ratio LDL HDL cholesterol ratio Triglycerides (mg dL) BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters) BP, blood pressure HDL, high-density lipoprotein LDL, low-density lipoproteins mo, months. SI conversions to convert glucose to mmol L, multiply by 0.0555 HDL, LDL, and total cholesterol to mmol L, multiply by 0.0259 insulin to pmol L, multiply by 6.945 and triglycerides to mmol L, multiply by 0.0113. *For Atkins group, the actual numbers of records available were 31 at 2 months, 22 at 6 months, and 21 at 12 months for Zone group, 33 at 2 months, 26 at 6 months, and 26 at 12 months for Weight Watchers group, 33 at 2 months, 30 at 6 months, and 26 at 12 months for Ornish group, 29 at 2 months, 21 at 6 months, and 20 at 12 months. BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters) BP, blood pressure HDL, high-density lipoprotein LDL,...

Laboratory Findings in CR Nonhuman Primates

The characteristics of CR monkeys are summarized in Table 2 72 and Fig. 12A-C 73 . CR monkeys weigh less 74 and have less total and abdominal obesity than controls 75 . In addition, CR reduces body temperature and induces a transient reduction in metabolic rate 76 . Young male CR monkeys also exhibit delayed sexual and skeletal maturation 72, 74 . In addition, several lines of evidence suggest that CR improves the disease risk in rhesus monkeys 72 . CR monkeys have reduced blood glucose and insulin levels and improved insulin sensitivity 75 . CR also reduces blood pressure and lowers the serum triglyceride and cholesterol levels 77 . In

Therapeutic Trials and Their Meta Analyses

During the 30-year evolution of therapeutic trials and meta-analyses, it is evident that (1) the clinical face of hypertension has considerably changed, from severe and malignant to milder forms of hypertension, including systolic hypertension in the aged (2) the number of classes of antihypertensive agents has also increased, as a function of the discovery and commercialization of new antihypertensive agents (3) the concomitant use of non-anti-hypertensive agents, such as statins, has also markedly increased, and (4) no consistent differences have been sought in the strategy of drug treatment between men and women despite the well-established lower CV risk in women 7 .

Pitavastatin Hypocholesterolemic [8386

Pitavastatin, launched last year for the treatment of hypercholesterolemia, belongs to the family of second-generation statins, also referred to as superstatins due to their improved efficacy as cholesterol lowering agents. Like other statins, pitavastatin reduces plasma cholesterol levels by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis in the liver. It is a more potent inhibitor of HMG-CoA reductase than the previously marketed statins and has the potential benefit of not undergoing significant metabolism by CYP3A4. Pitavastatin is synthesized in a multi-step sequence, including the key step of introducing the dihydroxyheptenoate side chain by cross-coupling of a 3-iodoquinoline intermediate with an alkenylborane reagent. Unlike rosuvastatin, the other statin introduced last year, pitavastatin has a high oral bioavailability ( 80 ). Plasma protein binding is also high for pitavastatin ( 95 ), and regardless of the dosing, the...

Metabolic Mechanism for OA

Hypertension was associated with the development of OA, particularly for bilateral knee disease (11,26). This study also suggested an association between bilateral knee disease and hypercholesterolemia and raised blood glucose. Similarly, after adjusting for age, slightly higher levels of plasma glucose were demonstrated in arthritic women than in normal controls (62). Nevertheless, most studies generally do not support an association between hypertension, raised serum cholesterol, glucose, and OA, and the data therefore remain inconclusive.

Tamibarotene Anticancer [9396

Development of resistance to ATRA is partly attributed to a progressive decrease in plasma drug concentration because of the rapid upregulation of its catabolism, and partly to an increased expression of cytoplasmic retinoid-binding proteins (CRABP) which limit the amount of free drug. In an attempt to overcome these problems, tamibarotene was synthesized by the introduction of heteroatoms into ATRA-like structures. Tamibarotene exhibits an improved selectivity profile as compared with ATRA. It has slightly higher affinity for RARa (EC50 45 nM) than RARp and RARg (EC50 23 5 and 591 nM, respectively), and it is inactive against RXR. In addition, tamibarotene has little affinity for CRABPs and is active against CRABP-rich ATRA-resistant cells. In a clinical study involving 24 APL patients who had relapsed from ATRA induced complete remission (CR), 6mg m2 day of oral tamibarotene resulted in 14 (58 ) patients achieving a second CR. Adverse events included retinoic acid syndrome,...

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