High Cholesterol Natural Medicine

Beat Cholesterol Guide

Beat Cholesterol In 30 Days is the latest program that teaches people how to control their cholesterol levels, and reduce their risk of a heart attack dramatically. The program also provides people with easy and simple exercises to get lean, fit, and healthy. In addition, this program is designed by Scott Davis, an alternative health expert and medical researcher who has over 14 years of experience in the healthcare industry. Davis shows that lowering your cholesterol is a straightforward process: changing your diet according to the guidelines in the guide will reduce your cholesterol to healthy levels. There's nothing relative or interpreted in this book. Certain foods will make your cholesterol levels better. But some will make them worse, and Davis makes it easy to determine and identify the cholesterol-raising culprits in your cupboard. It includes simple dieting tips that naturally reduce cholesterol, superfoods that will reduce cholesterol quickly, and much more. As you go through the e-book, you discover facts about foods and exercise that are often simple but life-changing (such as how to maximize results from your workouts to get better results from less exercise) as well as disturbing truths about the less-considered dangers of many prescription medications. Read more here...

Natural Cholesterol Guide Overview

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Section C Statins Chapter 153

Statins and the Microvasculature 1035 Introduction Mechanisms of Action Effects of Statins on the Microvasculature Statins as Antioxidants Effects on Other Vasoactive Mediators Regulation of the Endothelial Cytoskeleton by Statins Statin Effects on Vascular Wall Cell Proliferation and Survival Anti-inflammatory Effects of Statins Antithrombotic Properties of Statins Potential Clinical Applications of Statins Targeting the

IIIC Stimulus Induced Responses in Hypercholesterolemia

Although the mechanisms underlying the exaggerated responses to hypercholesterolemia remain poorly defined, there is evidence that implicates an enhanced oxidant stress in this response. Kurose et al. (59) demonstrated (using the oxidant-sensitive fluorochrome DHR-123) a more marked increase (12-fold) in oxidant production from venules after I R in hypercholesterolemic mice compared to their normocholestero-lemic (6-fold) counterparts. Furthermore, pretreatment of hypercholesterolemic animals with either oxypurinol or SOD largely prevented the enhanced oxidant stress and exaggerated leukocyte trafficking following I R, suggesting that XO is the major source of ROS under these conditions. Since both I R and hypercholesterolemia are also associated with a reduction in endothelial-derived NO, the enhanced oxidant stress observed in hypercholesterolemic animals exposed to I R is likely a consequence of the combined effect of these two deleterious conditions. Oxidant stress is also often...

Linkage Between Microvascular And Macrovascular Responses To Hypercholesterolemia

The sections above provide an overview of the many inflammatory and thrombogenic changes that occur in the vasculature during hypercholesterolemia. These include alterations on both the arteriolar and venular sides of the microvasculature, unlike in large vessels where arteries (and not veins) appear to be the primary site of injury during hypercholesterolemia. In addition, the microcirculation responds to hypercholeste-rolemia within 1-2 weeks, whereas in atherosclerosis-prone areas of the aorta and other large arteries, changes are observed only after long-term hypercholesterolemia. Despite these differences, many similarities exist between the mechanisms involved in the microvascular and macrovascular responses to elevated cholesterol levels. These include the induction of CAMs, leukocyte, and platelet recruitment and the release of cytokines chemokines. Of most relevance to the topic discussed here is the finding that some of the earliest detectable changes in both small and large...

Antioxidant Strategies In Hypercholesterolemia

While there have been relatively few positive findings or mechanistic insights with vitamin therapy in humans, the use of slow-release vitamins was recently found to delay the progression of atherosclerotic lesion development (65). However, high levels of certain vitamins may also alter the blood lipid profile in a manner that could outweigh any antioxidant benefit (66). Interestingly, evidence is emerging that drugs developed for other purposes, for example HMG-CoA reductases (statins), AT1 receptor antagonists, aspirin, and 17P-estradiol, possess properties that reduce oxidative stress independently or as a result of their targeted action. The most extensively investigated of these, i.e., statins and AT1 receptor antagonists, are discussed below. Statins were first introduced as lipid-lowering drugs, by virtue of their blocking action on the conversion of HMG-CoA to mevalonoate, the substrate for cholesterol. However, recently, it has become increasingly apparent that...

Hypercholesterolemia and Capillaries

In response to the changes in arteriolar tone that accompany hypercholesterolemia, red blood cell velocity is reduced. This leads to erythrocyte aggregation and stasis in smaller microvessels. Humans with elevated blood cholesterol levels are said to exhibit reduced capillary perfusion, which likely reflects a diminished red blood cell velocity in capillaries. Recent work suggests that NO-dependent pathways contribute to the impaired capillary perfusion during hypercholesterolemia. There is evidence that leukocyte accumulation in downstream venules may also contribute to the impaired capillary perfusion during hypercholes-terolemia, possibly through the release of inflammatory mediators. Administration of oxLDL to otherwise normal animals promotes the degradation of the endothelial glycocalyx in capillaries. Platelets adhere to the endothelial cells of these damaged capillaries. The glycocalyx breakdown and resultant platelet adhesion can be inhibited by superoxide dis-mutase (SOD)...

Hypercholesterolemia and Postcapillary Venules

Although large veins appear to be relatively unaffected by acute or chronic elevations in blood cholesterol concentration, postcapillary venules in the diameter range of 20 to 40 mm exhibit profound changes in response in these conditions. Some of the alterations in signaling and inflammatory pathways induced in arterioles by hypercholesterolemia are also manifested in venules. For example, the reduced NO bioavailability and elevated ROS production are seen in both segments of the microvasculature. However, the consequences of these changes vary between the vascular segments, with NO and ROS exerting minimal influence on the diameter of venules while exerting a profound effect on arte-rioles. In venules, NO exerts a major influence on the expression of cellular adhesion molecules and consequently serves to minimize the adhesive interactions between circulating blood cells and venular endothelium. However, during hypercholesterolemia the expression of several adhesion molecules is...

Exaggerated Inflammatory Responses during Hypercholesterolemia

Hypercholesterolemia and can be blocked by pretreatment with either SOD or a xanthine oxidase inhibitor (allopuri-nol). This suggests that O2- generated from xanthine oxidase mediates the leukocyte accumulation elicited by hypercholesterolemic tissues exposed to I R. Hypercholes-terolemia also enhances the P-selectin upregulation that is normally elicited by I R. In addition, the hypercholes-terolemia-induced exacerbation of inflammation is seen when tissues are challenged with either lipid mediators (leukotriene B4 and PAF) or cytokines such as TNF-a. It has also been shown that hypercholesterolemia exacerbates the protein extravasation in venules induced by various inflammatory stimuli, and that this may be due to the enhanced leukocyte recruitment. However, administration of oxLDL in the local arterial supply of tissues exposed to I R promotes leukocyte adhesion and emigration, without an accompanying increase in albumin extravasation. Although oxLDL is able to induce most of the...

Relevance of Hypercholesterolemia Induced Microvascular Responses to Atherosclerosis

Many of the inflammatory responses and pathways that are initiated in the microvasculature by hypercholes-terolemia have also been implicated in the development of atherosclerotic plaques. Whether the early inflammatory responses seen in venules influence the development of lesions in large vessels remains unclear. Since the inflammatory responses to hypercholesterolemia appear to be experienced by all tissues in the body, it appears tenable that the large endothelial surface area (> 500 m2) within the microvasculature may serve as a motor that drives the systemic immune response, ultimately leading to lesion development in large arteries. It is clear, however, that this risk factor, while rendering tissue more likely to experience an ischemic episode through the development of atherosclerosis, also predisposes organs to greater microvascular dysfunction and more tissue injury following a given ischemic insult. Hence, an improved understanding of the mechanisms that underlie the...

Reverse Cholesterol Transport by HDL Good Cholesterol Protects Against Atherosclerosis

Epidemiological evidence indicates that the concentration of HDL cholesterol in the plasma is inversely correlated with the risk for atherosclerosis and cardiovascular disease. Furthermore, transgenic overexpression of apolipoprotein A-I, As discussed earlier, HDL can remove cholesterol from cells in extrahepatic tissues, including artery walls, and eventually deliver the cholesterol to the liver either directly by selective lipid uptake mediated by the receptor SR-BI or indirectly by transferring its cholesterol to other lipoproteins that are ligands of hepatic endocytic receptors (see Figure 18-13c). The excess cholesterol can then be secreted into the bile and eventually excreted from the body (see Figure 18-11). Figure 18-22 summarizes this process, called reverse cholesterol transport, which lowers both the intracellular cholesterol in macrophages and the total amount of cholesterol carried by the body, thereby directly and indirectly reducing foam cell formation. In a sense,...

Statins as Antioxidants

The NADPH oxidase is a major source of O2- within the vascular wall, and Rac-GTPase is an important regulator of this enzyme in EC, VSMC, and phagocytes. Statins block the translocation of GTP-bound Rac to the membrane, consequently reducing transcription of critical NADPH sub-units and vascular wall production of ROS in response to various stimuli, such as angiotensin II and PKC agonists. An increase in catalase expression has also been observed in aortic walls of spontaneously hypertensive rats treated with statins 4 . A direct scavenging effect of fluvastatin on hydroxyl and superoxide radicals has been described, providing another antioxidant mechanism of statins.

Antiinflammatory Effects of Statins

Statins have been shown to possess multiple antiinflammatory actions that play an important role in mediating their vasculoprotective properties. Conditions associated with impairment of NO availability and increased oxidant stress, such as hypoxia and ischemia-reperfusion, induce an inflammatory endothelial phenotype characterized by enhanced expression of the surface adhesion molecules, P-selectin, ICAM-1, and VCAM-1. By enhancing eNOS function and reducing ROS, statins decrease expression of adhesion molecules and inhibit leukocyte-EC binding and transmigration in vitro at concentrations as low as 0.01 M. In animal models, statins decrease leukocyte adhesion within the microvasculature in response to thrombin, bacterial toxins, and low-dose LNMA. High-dose LNMA reverses these effects, and they are not observed in eNOS knockout mice. Statins may directly inhibit the transcription factors NF-kB and activator protein-1 (AP-1), and induce the nuclear receptors PPARa and g which...

Potential Clinical Applications of Statins Targeting the Microvasculature

The pleiotropic actions of statins have been postulated to account for the impressive clinical benefits observed in atherosclerotic cardiovascular disease independent of cholesterol lowering. Improved microvascular function likely contributes to these benefits. Hypercholesterolemia, diabetes, and hypertension are all associated with impaired endothelium-dependent vasodilation, which is improved within days by statin therapy in humans. The stimulation of angiogenesis by these agents would be expected to promote the normal adaptive response of the microcirculation to chronic ischemia. In a murine model of hind limb ischemia, simvastatin at a dose of 0.1 mg kg promoted new capillary formation and collateral flow. The microcirculation also plays an important role in the progression of large vessel plaques. The vasa vasorum of these arteries is the source of inflammatory cells that can promote plaque rupture. Statins may help to stabilize such lesions. Some investigators have speculated...

Statins Can Cholesterol Metabolism Modify the Pathophysiology of AD

Statins are among the most successful medications available in the pharmaceutical formulary. Statins are extraordinarily important tools for reducing morbidity due to cardiovascular disease, such as myocardial infarction and transient ischemic attacks (Shepherd et al., 2002). Statins have also been shown to reduce osteoporosis (Rejnmark et al., 2002). Statins might also reduce inflammation (Marz & Koenig, 2003). Their relative safety combined with putative efficacy makes them a very appealing prospect for therapy of AD. Some of the clinical benefits related to statin treatment are attributed to the pleiotropic actions that arise from inhibiting cellular cholesterol synthesis. Less cholesterol leads to less atherosclerosis, but the cardiovascular benefit of statins appears to extend beyond the simple reduction of LDL cholesterol. Many membrane proteins require cholesterol-rich environments. Some of these proteins, such as P- and y-secretases, are thought to be essential for the...

LDLRIndependent Uptake of LDL Bad Cholesterol Leads to Formation of Foam Cells

Develop and accumulate to form microscopically visible early fatty streaks. Given these facts, you might initially guess that LDLR-mediated endocytosis is responsible for foam cell formation, but there are two powerful reasons why it cannot be true. First, LDLR activity is under cholesterol-dependent, SREBP-controlled feedback regulation, which maintains cellular cholesterol levels within a narrow range. Intracellular cholesterol levels far below those seen in foam cells prevent transcriptional activation of the LDLR gene by the insig-1(2) SCAP SREBP pathway (see Figure 18-17). The consequent low level of LDLR expression prevents massive intracellular cholesterol buildup. Second, in familial hyper-cholesterolemic patients who lack LDLR activity and consequently have high plasma LDL levels, the onset of atherosclerosis is at much younger ages and its progress is dramatically accelerated compared with normal people. Clearly, the formation of foam cells in these patients does not require...

Effects of Statins on the Microvasculature

Statins increase EC eNOS protein levels in a time- and concentration-dependent manner. As little as 0.1 mmol L of simvastatin induces a nearly twofold increase in eNOS expression after 48 hours. A post-transcriptional mechanism is involved since eNOS mRNA stability increases without changes in gene transcription. Statins prevent the downregu-lation of eNOS induced by hypoxia and oxidized LDL. These effects are reversed by provision of either mevalonate or GGPP. Statin treatment also rapidly (within 1 hour) The role of inducible NOS II (iNOS) in the microcirculation is controversial. Whereas large quantities of NO contribute to hypotension in septic shock and can induce nitrosative tissue damage, there is evidence that iNOS-derived NO attenuates leukocyte-endothelial adhesion. Statins (1-10 mM) enhance cytokine-mediated induction of iNOS in VSMC and perhaps other cell types. In contrast, reduced iNOS induction by cytokines is noted in EC and macrophages.

Lipid Lowering Drugs Statins Fibrates

Hydroxymethylglutaryl coenzyme-A (HMGCoA) reductase inhibitors, better known as statins, are the most potent lipid-lowering agents, consistently documented to prevent or reduce cardiovascular events in primary and secondary prevention (168-170). The therapeutic potential of this type of drug is probably far greater than previously anticipated (171). Many of the nonlipid lowering effects of statins could be of major relevance to a variety of disease processes. For example, statins enhance nitric oxide production and improve endothelial function, display anti-inflammatory potency, inhibit integrins, and lower circulating adhesion molecules (172,173). As with statins, fibrates have also been shown to reduce coronary risk (LOCAT study) the beneficial nonlipid effects with respect to atherosclerotic prevention include antithrombotic effects (decrease in fibrinogen and PAI1), anti-inflammatory activity (inhibition of TNF-a-induced endothelial expression of VCAM-1 and IL6), and decrease in...

Analysis of Familial Hypercholesterolemia Revealed the Pathway for Receptor Mediated Endocytosis of LDL Particles

Some of these experiments compared LDL metabolism in normal human cells and in cells from patients with familial hypercholesterolemia (FH), a hereditary disease that is marked by elevated plasma LDL cholesterol and is now known to be caused by mutations in the LDLR gene. In patients who have one normal and one defective copy of the LDLR gene (heterozygotes), LDL cholesterol is increased about twofold. Those with two defective LDLR genes (homozygotes) have LDL cholesterol levels that are from fourfold to sixfold as high as normal. FH heterozygotes commonly develop cardiovascular disease about 10 years earlier than normal people do, and FH homozygotes usually die of heart attacks before reaching their late 20s. I Here, we illustrate how analysis of the cellular defects underlying familial hypercholesterolemia can illuminate normal cellular processes. First let's consider typical cell-culture experiments in which the interactions of LDL with normal and FH homozygous cells were examined...

Oxidative Stressgenerating Systems In Hypercholesterolemia

Many of the enzymes involved in ROS production during hypercholesterolemia-induced oxidative stress have been identified, including NAD(P)H oxidase, xanthine oxidase (XO), myeloperoxidase, lipoxygenase, and endothelial nitric oxide synthase (eNOS). These pathways produce substantial quantities of ROS such as O2 and HOCl, overwhelming the capacity of endogenous antioxidants such as superoxide dismutase (SOD), catalase, and NO, thereby resulting in an oxidative stress. Evidence for the participation of the above mechanisms is derived from several animal models and human studies, using both direct measurements and pharmacological inhibitors. Indeed, the excess levels of oxi-dants may propagate the response to hypercholesterolemia by promoting the oxidative modification of LDL, which exacerbates many of the inflammatory consequences. An increased production of O2 has been demonstrated in arteries of hypercholesterolemic animals (5). This can be attributed to...

Hypercholesterolemia and Arterioles

Under normal physiological conditions, basal NO production by endothelial cells maintains vascular tone and inhibits inflammation. However, during hypercholes-terolemia, several events occur that negatively influence the vasodilatory role of NO in arterioles. Although the concentration of L-arginine, the substrate for NO synthase (NOS), is not reduced during hypercholesterolemia, the interaction between L-arginine and endothelial NOS may be blocked by the endogenous inhibitor asymmetric dimethylarginine (ADMA), the levels of which are increased during hypercholesterolemia. The elevated ADMA levels likely result from the diminished activity of dimethylarginine dimet-hylaminohydrolase (DDAH), which normally degrades ADMA, that accompanies hypercholesterolemia. Furthermore, the NOS enzyme cofactor tetrahydrobiopterin (BH4) is also reduced during hypercholesterolemia, which would further reduce the bioavailability of NO. The net effect of these changes in both animal and human subjects...

Regulation of the Endothelial Cytoskeleton by Statins

In addition, we have observed cortical actin ring enhancement associated with increased translocation of cortactin to the cell periphery in statin-treated pulmonary EC that persists after thrombin stimulation. This effect has previously been shown to be mediated by Rac activation through Edg receptor agonists, such as sphingosine 1-phosphate and shear stress. Indeed, statins increase GTP-bound (activated) Rac in whole-cell lysates, whereas membrane-bound Rac is reduced. Prenylation of Rac is required for its attachment to membranes and activation of certain downstream effectors such as NADPH oxidase, but also reduces its binding to Rho-GDI (guanine nucleotide dissociation inhibitor), which normally maintains Rac in its inactive GDP-bound state 5 . Statins may also alter various guanine nucleotide exchange factor proteins (GEPs) or GTPase-activating proteins (GAPs) that positively regulate Rho family activity. Thus, some functions of Rac, such as its effects on cytoskeletal...

Antithrombotic Properties of Statins

Activation of thrombotic processes contributes to microvascular dysfunction in a variety of disease states such as sepsis and ischemia-reperfusion. Statins inhibit platelet activity by several mechanisms, including increased endothelial NO and adenosine release and decreased platelet thromboxane production and cholesterol content. Tissue factor expression and activity in response to thrombin is reduced in EC by simvastatin at concentrations as low as 100 nM. The fibrinolytic system may also be favorably affected by statins. An increase in tissue plasminogen activator and a decrease in plasminogen activator inhibitor type I in EC in response to statins have been demonstrated, but these effects require fairly high concentrations and human studies have been inconsistent.

Food and Drug Administration Rockville Maryland USA

Provide a greater understanding of human health and the causes of diseases at a genomic or molecular level. This would address the well-known heterogeneity of disease states that underlies the wide interindividual variation in efficacy observed with many common treatments. For example, incomplete or absence of response occurs in 30-50 of eligible patients with hypercholesteremia who are treated with statins. With greater insights into health and disease, sponsors would be more likely to identify a target protein or receptor and to find the best NME to provide preventive, curative, or palliative treatment for patients.

Obesity as a Chronic Disease

Along with genetics, except for certain medical conditions, most patients' obesity is the result of an unhealthy lifestyle of overeating and lack of physical activity. Fortunately, improved medical management has lowered the prevalence of some cardiac risk factors, especially among obese patients. From 1962 to 2000, hypercholesterolemia was reduced among obese patients 21-percentage-points (39 vs 18 ), and hypertension by an 18-percentage-point reduction (42 vs 24 ) 5 . Yet even with improved medical management of comorbidi-ties associated with obesity, the estimated number of excess deaths in 2000 associated with oesity was 111,909 6 .

Health Promotion And Disease Prevention

The concept of disease prevention is more specific and comprises primary, secondary and tertiary prevention (12). Primary prevention is defined as preventing the disease or stopping individuals from becoming at high risk. Universal and selective preventive interventions are included in primary prevention. Universal primary prevention targets the general public or a whole population group without an identified specific risk (e.g. iodine supplementation programmes to prevent neurological and other disorders caused by iodine deficiency). Selective primary prevention targets individuals or subgroups of the population whose risk of developing disease is significantly higher than average, as evidenced by biological, psychological or social risk factors (e.g. prevention of stroke through adequate management of hypertension, diabetes and hypercholesterolemia). Secondary prevention aims at decreasing the severity of disease or reducing risk level or halting progression of disease through early...

Who Should Give Dietary Advice

Self-help resources, in terms of reducing total serum cholesterol in adults. The reviewers electronically searched the Cochrane Library, MEDLINE, EMBASE, CINAHL, Human Nutrition, the Science Citation Index, and the Social Sciences Index. They also hand-searched conference proceedings and contacted experts to find all of the randomised controlled trials through 1999. Randomised controlled trials that compared the effects of dieticians' advice on serum cholesterol levels with the effects of advice by other health professionals or self-help packages were selected. Decisions on inclusion were duplicated by two independent reviewers and disagreements were resolved by discussion or by a third reviewer. Two reviewers independently extracted the data from included studies and assessed trial quality. Patient follow-up of at least 80 in both groups was achieved for four studies only, but blinded and reliable assessment of blood cholesterol was done for all studies. Most studies ensured that...

The Obesity Epedemic in America

The significance of overweight or obese BMI is that it correlates with an increased relative risk for developing chronic diseases and cancers. The data from a 10-year follow-up of the combined Nurses' Health Study and the Physician's Health Professionals Follow-Up Study show men and women who are overweight, compared to a normal BMI of 18 to 24.9, are more likely to develop gallstones, hypertension, high cholesterol, and heart disease. The relative risk (RR) for developing diabetes of an individual with a BMI 35 or greater is 20 times greater than for someone with a normal BMI 18 . The American Heart Association's scientific statement on obesity as an independent risk factor for heart disease states obesity not only relates to but independently predicts coronary atherosclerosis 19 . The relative risk (RR) of cardiovascular death increases with BMI. A BMI of 19 to 21.9 has an RR of 1, and a BMI > 32 has a RR over 3 20 .

Protective Dietary Changes For Cardiovascular Disease Patients

A further systematic review examined the effects of omega-3 fats in diabetics.15 Unfortunately, no studies or large subgroups of published studies assess the effects of omega-3 fats on disease endpoints in diabetics. There is no evidence of detrimental effects of cardioprotective doses of omega-3 fats on glycemic control or LDL cholesterol levels (higher levels of supplementation have been used to reduce triglyceride levels the smaller cardioprotective doses mentioned above may well save lives of diabetics but do not alter triglycerides significantly). More evidence would be useful to clarify this issue. While dietary advice has a role to play in normalizing abnormal serum lipids in people with cardiovascular disease, aspects of diet that clearly protect against death and disease should be given greater emphasis than lipid reduction in this group. Dietary changes are likely to result in reductions of total cholesterol of about 5 ,25-27 while statin trials reduce total cholesterol by...

High Plasma Cholesterol

In the early 1990s, high cholesterol was found to be associated with the presence of ApoE4 alleles in clinically diagnosed Alzheimer's disease (Czech et al., 1994). In particular, high levels of LDL cholesterol resulted in a higher risk of dementia and stroke and the question posed was whether the administration of statins could diminish the incidence of these conditions (Moroney et al., 1999). The influential epidemiologic study of Wolozin and collaborators (Wolozin, Kellman, Ruosseau, Celesia, & Siegel, 2000) demonstrated that the patients taking the cholesterol-lowering drugs, which act as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, better known as statins, show a 60-73 lower prevalence of probable AD. These findings were followed by numerous studies regarding the impact of high cholesterol in creating favorable conditions for the generation of Ap peptides and further clinical investigations on the impact of statins (Sjogren & Blennow, 2005 Wolozin, 2004)....

Step I and step II diets

Dietary therapy should be initiated in patients who have borderline-high LDL cholesterol levels (130 to 159 mg dL) and two or more risk factors for coronary heart disease and in patients who have LDL levels of 160 mg dL or greater. The objective of dietary therapy in primary prevention is to decrease the LDL cholesterol level to 160 mg dL if only one risk factor for coronary heart disease is present and to less than 130 mg dL if two or more risk factors are identified. In the presence of documented coronary heart disease, dietary therapy is indicated in patients who have LDL values exceeding 100 mg dL, with the aim of lowering the LDL level to 100 mg dL or less.

DHMGCoA reductase inhibitors

Lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and cerivastatin (Baycol) are HMG-CoA reductase inhibitors, or statins, that inhibit cholesterol synthesis. These agents lower total, LDL and triglyceride cholesterol and slightly raise the HDL fraction. While these agents are generally well tolerated, 1 may develop elevated hepatic transaminase levels, which may necessitate discontinuation of the drug. Other adverse effects include myopathy (0.1 ) and gastrointestinal complaints. 2. Atorvastatin (Lipitor) may exert a greater effect on lowering LDL cholesterol, total cholesterol and triglycerides. Statins should generally be taken in a single dose with the evening meal or at bedtime.

Present and Future Pharmacological Treatment of Alzheimers Disease

The majority of current ongoing research efforts are geared toward developing disease-modifying therapies, i.e., addressing the causative aspects of the disease, which should profoundly modify or prevent the onset of AD. A great many potential disease-modifying therapies for AD are currently being explored in academic institutions, and by the biotech and the pharmaceutical industries. The chapters collated in this book are representative examples of such efforts. They deal with a variety of targets and are based on a defined rationale, as explained in these contributions. Putative therapies with solid preclinical proof of concept eventually find their way to clinical trials, which in the case of AD have the inherent complication of a slowly progressing disease. This means the planning of long-term and well-structured, expensive, clinical trials. The chapter by Serge Gauthier specifically addresses these issues for the investigation of drugs for both symptomatic and disease-modifying...

Pharmacogenetic Targets In Cardiovascular Disease

Atherosclerosis is, at least in part, attributed to an underlying immune-mediated process with onset early in life, ultimately leading to severe clinical manifestations, such as myo-cardial infarction, unstable angina, and cerebral stroke. The increased incidence of cardiovascular events in the western societies is attributed to the underlying immune process, which is amplified by additional cardiovascular risk factors, such as hypercholesterolemia, hypertension, smoking, diabetes, and obesity, which by themselves have their own genetic background. This section provides a summary of some of the key issues for a full discussion, see the chapter on cardiovascular disease.

Era of Drug Interactions and PKPD Relationships

Serious interactions between mibefridil and certain cholesterol lowering statin drugs resulted in the removal of mibefridil from the market. Mibefradil is a potent inhibitor of the metabolism of lovastatin and simvastatin and if either of these drugs is taken together with mibefridil, they can cause potentially life-threatening rhabdomyolysis related to much higher exposure to the statin drug due to inhibited metabolism caused by mibefridil 37 .

Factors That Influence the Numbers of Circulating Endothelial Progenitors

Endothelial cells to sites of injury. G-CSF, GM-CSF, and erythropoietin, cytokines already in use clinically to promote mobilization of hematopoietic cells, can also increase EPCs. EPC mobilization can also be increased by HMG-CoA reductase inhibitors (statins). Further dissection of the mobilization of circulating EPCs by Heissig and colleagues shows that mobilization of both hematopoietic and endothelial precursors is dependent on MMP-9-mediated release of soluble kit ligand (sKitL) in the bone marrow.

Genetic Counseling The Discipline and the Provider

As our knowledge of genetic disorders and complex inheritance patterns has expanded, so have the options for molecular-based genetic testing. With this growth, complex ethical and social issues have come to the forefront, such as genetic discrimination. As medical research has advanced, we have come to appreciate the strong influence of genetics in common disorders, such as cancer, diabetes, Alzheimer disease, asthma, and hypercholesterolemia. The burden of passing on an abnormal gene or trait is not limited to individuals and families faced with rare disorders of Mendelian inheritance. It is a reality for everyone. Increasing anxiety about genetic risk for disease and concern about passing on abnormal genes to future generations for common conditions has expanded the need for genetic counseling. There are now subspecialties of genetic counseling, such as prenatal, pediatric, cancer, and neuro-genetics. Genetic counselors also are working in clinical molecular diagnostic laboratories...

Etiology And Risk Factors

The main risk factor for most forms of dementia is advanced age, with prevalence roughly doubling every five years over the age of 65 years. Onset before this age is very unusual and, in the case of AD, often suggests a genetic cause. Single gene mutations at one of three loci (beta amyloid precursor protein, presenilinl and presenilin2) account for most of these cases. For late-onset AD both environmental (lifestyle) and genetic factors are important. A common genetic polymorphism, the apolipoprotein E (apoE) gene e4 allele greatly increases risk of going on to suffer from dementia up to 25 of the population have one or two copies (4, 5). However, it is not uncommon for one identical twin to suffer from dementia and the other not. This implies a strong influence of the environment (6). Evidence from cross-sectional and case-control studies suggests associations between AD and limited education (7) and head injury (8, 9), which, however, are only partly supported by longitudinal...

Saccharomyces cerevisiae

The value of these toolboxes for gene function identification, which is now undisputed, was first validated in the above original studies. The simultaneous assay of 558 homozygous deletion strains - a subset of the gene deletion mutants collection - for growth in rich and minimal media demonstrated that reliable quantitative fitness data can be simultaneously obtained under various conditions for large number of mutants 19 , as was later abundantly documented. Similarly, 7680 transposon insertion haploid strains were scored, using phenotypic macroar-rays, for 20 different phenotypes, which confirmed or provided novel functional information for 407 genes 18 . In addition, protein localization was analyzed in 1340 diploid strains carrying in-frame hemagglutinin epitope tag insertions 18 , illustrating the extreme versatility of this approach. Globally, these mutant collections, which can be easily obtained by any researcher, have encouraged an unparalleled blossoming of genome-wide...

Role of Endothelial [Ca2i in EDHFMediated Responses in Pathology

An increasing number of studies demonstrate potentiated EDHF-mediated responses following a variety of pathological conditions, including ischemia reperfusion (I R), hypercholesterolemia, and congestive heart failure. The mechanism by which this potentiation occurs remains largely unknown. However, in cerebral I R, the potentiated EDHF-mediated dilations are accompanied by augmented endothelial Ca2+ responses 12 . In this case, for a given agonist concentration, there was a greater increase in

Prevention Of Coronary Heart Disease As The Goal

Atherosclerosis is the primary cause of coronary heart disease. Markedly lowering blood cholesterol can halt and even reverse to some extent the progression of atherosclerosis. For these reasons, prevention should be the goal, with the focus on decreasing elevated blood cholesterol. About 20 of Americans between 20 and 75 years of age have blood total cholesterol levels above 240 mg dL, a level requiring management, and up to 40 of some middle aged groups have this elevation. Although hypercholesterolemias are linked to specific genetic mutations, most have a multifactorial basis that can respond to lifestyle changes. Even though the physician is justified in immediately prescribing a cholesterol-lowering drug to patients with very high blood cholesterol and additional risk factors, strong advice should also be given on the need and benefits of adding life style changes. These changes include reduction of body weight decreased dietary total fat, choles WHEN TO TREAT...

Drug Interactions

Most of the statins (lovastatin, simvastatin, atorvas-tatin, and cerivastatin) are metabolized by the cytochro-mal P450 3A4 system of intestines and liver to more water-soluble metabolites that are excreted in both the bile and urine. Drugs that inhibit P450 3A4, such as itraconazole, cyclosporine, and erythromycin, can vastly (10fold) increase plasma statin levels and thus increase the risk of toxicity. Unexpectedly, grapefruit juice can inhibit intestinal metabolism of the statins and can result in an 8- to 10-fold increase in simvastatin serum levels. Since fluvastatin is metabolized by cytochrome P450 2C9, which is also responsible for metabolism of warfarin, warfarin toxicity may be increased if these drugs are simultaneously given. Grapefruit juice should obviously not be consumed within several hours of statin administration. Drugs that induce the P450 3A4 system, such as barbiturates, can accelerate statin metabolism and suppress statin blood levels.

Mechanism of Action

Used alone, nicotinic acid can decrease plasma LDL cholesterol levels by 15 to 30 . It can also be used in combination therapy with the statins or the bile acid-sequestering resins to augment reduction of very high LDL levels. Because nicotinic acid can lower plasma triglycerides by 40 or more, it is useful in treating familial hypertriglyceridemia type IV (Table 23.3), and in combination with the statins it is useful in treating combined hyperlipidemia type lib. As described later with the fibrates, patients with high plasma triglycerides plus low HDL are at increased risk for CHD. Nicotinic acid is useful for treating these patients, since it can both lower triglycerides and raise HDL.

When to Treat Hypertriglyceridemias

The guidelines for use of drugs to treat familial hyper-triglyceridemia type IV are less well defined than those for hypercholesterolemia. One should account for plasma HDL in deciding to treat hypertriglyceridemias with the intent of decreasing the risk for CHD. Moderate hypertriglyceridemia (200-500 mg dL) without low HDL may not be an independent risk factor for CHD. However, the results of a recent clinical trial indicate that hypertriglyceridemia is an independent risk factor for ischemic stroke. Results of the Helsinki Heart Study showed that the reduced risk of CHD with use of gemfibrozil (discussed later) was correlated with elevation of HDL plus reduction of VLDL triglyceride rather than reduction of LDL cholesterol. Gemfibrozil has little effect on plasma LDL. Low HDL cholesterol (< 35 mg dL) is an independent risk factor for CHD. HDL appears to antagonize atherogenesis by at least two mechanisms. HDL can mobilize cholesterol from extrahepatic cells (such as arterial wall...

Materials and methods

History of psychosis, or a history of schizophrenia, schizoaffective disorder or bipolar disorder, a serious concomitant medical condition, a history of seizures or misuse of alcohol or drugs (recent use of any psychotropic drugs within one month of baseline), clinically significant abnormalities in electrocardiogram or laboratory findings, or a serious risk of suicide. Combat-related symptoms included intrusive images of screaming soldiers, fire, bombing, rocketing, etc. Individuals taking cholesterol-lowering drugs were excluded. The procedures were fully explained and written informed consent was obtained from all patients. The local Ethics committee approved this protocol.

Effects of Pglucans on lipid metabolism

More data on the effect of dietary fibre on cardiovascular diseases have been gained from intervention trials. Over 50 studies have investigated the effect of P-glucans on blood cholesterol levels. Some investigators have also addressed the task to make overall evaluations on the relation between oat P-glucan intake and its cholesterol-lowering effects. A large meta-analysis of oat products and their lowering effects on plasma cholesterol was made by Ripsin et a .51 The included studies presented differences in study designs, oat products, doses of oats and control products, and subjects with different initial cholesterol levels, gender and age the influence of these parameters was assessed in the meta-analysis. To be included in the meta-analysis, studies had to be controlled and randomized and the control product had to have a low soluble fibre content. Moreover, the trial should also have included a dietary assessment and measurement of body weight. Twelve trials were included in...

Hcholf Diets And Cholesterol Metabolism

Convincing evidence from both cross-sectional and nutritional intervention studies indicates that plasma total cholesterol level is inversely related to CHO intake.11011 This effect is observed in normolipidemic and hyperlipidemic subjects1215 and in subjects with metabolic syndromes.16 It occurs independently of variations in total energy and cholesterol intake.11 However, both low density lipoprotein (LDL) and HDL cholesterol participate in this decrease of plasma cholesterol and the HDL over LDL cholesterol ratio is unchanged or sometimes decreased.10,11,14,15 This decrease in HDL cholesterol led some authors to question the actual benefits of high-CHO diets compared to diets high in monounsaturated fatty acids with respect to the prevention of atherosclerosis.8 An important question is whether it is possible to prevent at least in part this fall in HDL cholesterol and achieve a more favorable HDL over LDL cholesterol ratio by carefully choosing the amount and nature of the CHO...

BGlucans in the regulation of satiety and acceptance by consumers

The soluble oat p-glucan has been found to have positive effects on health, such as reducing blood cholesterol levels.49'51 The consumption of a hypocaloric diet containing oats over 6 weeks resulted in a greater decrease in systolic blood pressure, total cholesterol and LDL cholesterol than did a similar diet without oats.84 Oat p-glucans can also be used in controlling weight. Ingesting oat p-glucans can increase the viscosity of gut contents enhancing the feeling of fullness. Oat p-glucans can lower the rate at which nutrients are absorbed from the small intestine, delay gastric emptying and prolong the feeling of satiety.658586 The first effect occurs in the stomach, where swelling and water binding by the fibre causes distension that contributes to the feeling of satiety. In the small intestine, fat and protein or amino acids induce release of the gut hormone cholecystokinin, which delays gastric emptying, blunts glycaemic responses and enhances satiety.87 The effect is believed...

Cholesterol And Toxins

The concept that cholesterol can inactivate or neutralize a wide variety of toxins is not new. In 1981, Alouf identified cholesterol as an inactivator of multiple bacterial toxins.7 Chi et al. and Watson and Kerr showed that elevation of serum cholesterol actually served as a marker for a number of different toxic exposures.8,9 Studies by Kossman et al. and Bloomer et al. even demonstrated that exposure to the toxicity of pesticides would reliably elevate the cholesterol levels of those exposed individuals.10,11 Davies et al. also showed that dogs exposed to low levels of methylmercury developed progressively higher levels of cholesterol in the blood over time.12 A very reasonable conclusion from all of these studies considered When patients who presented with high cholesterol levels (over 240 mg ) had their mercury amalgams and sources of dental infection removed, these levels usually dropped dramatically within a few days. Generally, the only exceptions occurred in patients who...

Hcholf Diets And Triglyceride Metabolism

The concept of carbohydrate-induced hypertriglyceridemia emerged as soon as the first studies comparing plasma lipid concentrations during high-fat and high-CHO diets were performed in the 1950s.9 24 Since high TG level appears as an independent risk factor for coronary heart disease (CHD),25 this possible adverse effect raised, in addition to the decrease in HDL cholesterol, concerns about using high-CHO diets for the prevention of atherosclerosis.13

Effects Of Nondigestible Carbohydrates

Wolever et al. showed that propionate decreased the incorporation of 13C labelled colonic acetate in plasma TG in humans the effect on the incorporation in plasma cholesterol was not significant.79 Several studies showed that NDCs reduce TG concentrations in control humans, particularly while on high-CHO diets,80-82 and can also reduce cholesterol levels.82 Negative results have also been reported in normal subjects, probably because of low doses of CHOs and relatively high fat diets.83,84

Changes in lipid metabolism

And decreased catabolism of these lipids by low plasma post-heparin lipolytic activity. Hypercholesterolemia is explained by reduced clearance of low-density lipoproteins, reduced hepatic synthesis of cholesterol, and slowing down of secretion into bile ( B rgi and K nig 1988).

Practical Considerations Of Highcho Diets

Since high-CHO diets exert both favorable (reduction in total and LDL cholesterol) and potentially adverse (decrease in HDL cholesterol and increase in TG concentrations) effects on lipid metabolism, one is left to wonder whether the sum of these CHO-induced changes provides net benefits to a patient or population. No definitive answer yet exists, but some guidelines can help reduce the unfavorable effects of high-CHO diets 1. Weight loss should be advised for individuals on high-CHO diets because it would have beneficial effects on TG and HDL cholesterol concentrations. Such weight losses occur frequently because subjects spontaneously reduce their energy intake as a result of the increased volume of a low-fat diet. Otherwise, reduction of total energy intake should be advised.

Review Of Atherosclerosis

Atherosclerosis is a condition in which lipid (fat) deposits form on the inside of the arteries causing a decrease in the flow of blood through the arteries. The make up of these deposits is mostly cholesterol as a consequence of genetic and dietary factors which result in too much cholesterol. The arteries of most concern are the coronary arteries (those that supply the heart) and the carotid arteries (those that supply the brain). Hyperlipidemia is a condition of high levels of cholesterol, triglycerides, and or lipoprotein in the blood. The higher the levels in the blood, the greater the risk that they will deposit on the inside of arteries. Several studies have shown a correlation between cholesterol levels and premature heart disease. Studies have shown that each 1 reduction in serum cholesterol correlates with a 2 decline in the risk of myocardial infarction. For example, a 25 reduction in cholesterol will reduce the risk of myocardial infarction by 50 . Diet, exercise,...

Radiographic and Other Studies

Various medications can be tried, including bile-acid binding agents (cholestyramine, colestipol, antacids), phenobarbital, rifampin, ursodeoxycholic acid, antihistamines, and carba-mazepine. Efficacy is not uniform. Biliary diversion surgery is occasionally used in severe pruritus. Intractable pruritus may be an indication for transplantation. C. Hyperlipidemia and Xanthomas. More common with intrahepatic cholestasis than extrahepatic disease. Severe hyperlipidemia in Alagille disease is associated with atherosclerosis and renal lipi-dosis. Treat with bile-acid binding resins such as cholestyramine or ursodeoxycholic acid. No significant effect is seen with dietary saturated fat or cholesterol restriction, or with cholesterol-lowering agents.

Dyslipidaemic Lipid Profile

Patients with Type 2 diabetes have an abnormal lipid profile with high levels of LDL-cholesterol and triglycerides (TG) and a low level of HDL-cholesterol. Data from the Multiple Risk Factor Intervention Trial (MRFIT) (19) suggest that although levels of total cholesterol and LDL-cholesterol do not differ significantly between patients with and without diabetes, those with diabetes have higher concentrations of atherogenic small dense LDL-cholesterol particles.

Fat And Plasma Lipids

A high intake of saturated fatty acids has been associated with an increased incidence of CHD, presumably because a high saturated fat intake increases LDL-cholesterol and reduces HDL-cholesterol (27). In a review by Garg (26) monounsaturated fat diets compared to high-carbohydrate diets reduced fasting TG and VLDL-cholesterol by 19 and 22 respectively, with a modest increase in HDL-cholesterol without adversely affecting LDL-cholesterol (25).

Carbohydrate And Plasma Lipids

The literature contains conflicting findings, particularly in studies that contain > 20 of energy from sucrose or > 5 from fructose, where both sugars have been shown to raise TG concentrations. In studies containing amounts of sugars more typical of dietary habits in the Western world, elevated plasma TG concentrations are not usually observed (29). Interestingly, the glycaemic index of carbohydrate was significantly related to serum HDL-cholesterol in a retrospective cross-sectional study of 2200 middle-aged adults, where a low glycaemic diet was the only dietary variable related to the CHD risk factors measured (31).

Soya Protein Flavonoids And Phytooestrogens

The efficacy of soya and soya derivatives in lowering total cholesterol and LDL-cholesterol was recently supported by the US Food and Drug Administration (FDA) approving a health claim about the role of soya protein in reducing the risk of CHD. In 1999 the FDA finalised a rule that authorises the use on food labels and in food packages under FDA jurisdiction of the health claims concerning the association between soya protein and reduced risk of CHD '25g of soya protein a day, as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease' (37). Serum total cholesterol and LDL-cholesterol concentrations can be lowered by about 13 , plasma TG by 10 and HDL-cholesterol goes up by about 2 (38), and these beneficial effects are also seen in people with Type 2 diabetes (39). It is unclear if the benefits come from the main phyto-oestrogens found in soya, diadzein and genistein or from the soy protein itself. Epidemiological evidence suggests high intakes of...

Activation of aSecretase

That upregulation of a-secretase activity would preclude the formation of AP has recently been demonstrated in transgenic mice with moderate neuronal overexpression of ADAM-10 (Postina et al., 2004). In these mice there was increased secretion of sAPPa, reduced AP production, delayed plaque formation, and alleviation of cognitive deficits. A variety of agents have been shown to increase a-secretase activity in cell and animal models, including muscarinic agonists, protein kinase C activators, serotonin, glutamate, estrogen, testosterone, cholesterol-lowering drugs, and pituitary adenylate cyclase-activating polypeptide (PACAP) (Kojro et al., 2006 Vardy et al., 2005). Although some of these agents have been subject to clinical trial, there is as yet no evidence to support the routine use of any of them in the treatment of AD. Recently, it has been shown that the acetylcholinesterase inhibitors may exhibit some of their effects through stimulating the nonamyloidogenic a-secretase...

Cardiovascular Risk Factor Reduction

Patients with OSA are at increased risk of developing cardiovascular disease (21). In part, this is related to the concomitant presence of a variety of cardiovascular risk factors. That is, these patients have a high prevalence of the following male gender, smoking, diabetes, obesity, hypertension, and increased cholesterol (22). We recommend a low threshold for screening all patients with sleep apnea for the presence of hypercholesterolemia, hypertension, and diabetes and initiating appropriate therapy if indicated.

Metformin in Combination Therapy

A 1-year randomized double-blind study in 639 type 2 diabetic patients 13 showed clinically equivalent improvements in glycaemic control for the combination therapy of metformin and SU (HbA1c decrease 1.36 ) or pioglitazone and SU (HbA1c decrease 1.20 ). Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9 p 0.008) and increased HDL-cholesterol (14 vs. 8 p < 0.001) compared with metformin

Improvement of Cardiovascular Risk Profile by Metformin

During the last two decades a number of studies showed beneficial effects of metformin on traditional and non-traditional cardiovascular risk factors 11,47-58 . Metformin reduces fasting and postprandial insulin levels 3 , insulin resistance 4-6 and has beneficial effects on lipids, thrombosis and blood flow. Metformin has a weight-lowering effect 11,13,15 and reduces hypertriglyceridaemia 11 , elevated levels of PAI-1 47 , factor VII 49 , C-reactive protein 51,52,54 and intact proinsulin and des 31,32 proinsulin concentrations 48 . In randomized head-to-head comparisons (Fig. 2) of oral anti-diabetic drugs metformin treatment reduced triglycerides by 10 and increased HDL-cholesterol by 7 , whereas pioglitazone reduced triglycerides by 19 and increased HDL-cholesterol by 14 11 . By contrast, LDL-cholesterol decreased by 4 under metformin therapy, but increased by 8 under pioglitazone. Remarkably, HbA1c improvement was very similar and the prognostically important total cholesterol...

Metabolic disorders Obesity

More than one-third of Americans have a body weight of 20 per cent or more than their desirable weight. Approximately 50 per cent of women and 25 per cent of men are 'dieting' at any one time, generally with little prolonged benefit. Using standard treatments in university settings, only 20 per cent of obese patients lose around 9 kg (about 20 pounds) at 2-year follow-up and only 5 per cent of patients lose about 18 kg (40 pounds). (53) The majority of people who lose weight on a diet gain it all back. There is considerable mortality associated with obesity. This is predominantly due to coronary artery disease and associated risk factors, such as diabetes, hypertension, and hypercholesterolaemia. Numerous lines of evidence suggest strong genetic influences on the aetiology of obesity, (53) accounting for about two-thirds of the variations in weights among studied populations. However, environmental factors are also important. These include low physical activity levels and poor food...

Historical Perspectives On Carbohydrate

By the 1970s pharmaceutical treatments had expanded with the introduction of oral hypoglycaemic drugs and the average carbohydrate intake rose to about 40 energy. Prohibition of sucrose was now the main message. With extreme caution, several experimental studies compared higher carbohydrate diets (> 50 energy) with the traditional diabetes diet and found improved glucose tolerance or insulin sensitivity (12-14). In the late 1970s, there was a revolution in thinking about diabetic diets and a spurt of experimental studies indicated that high-carbohydrate diets were no worse, if not better, for people with diabetes because they lowered blood cholesterol levels (see below). By then, low-fat, high-carbohydrate diets were being recommended for the prevention and treatment of cardiovascular disease in the general population.

Current Recommendations For Carbohydrate Intake

10-15 monounsaturated fat (MUFA) (17). However, there is concern in some quarters that 50-55 of the total energy intake as carbohydrate may have adverse effects on blood triglyceride (TG), HDL-cholesterol and glucose levels compared with high-fat diets (> 35 total energy) enriched with MUFA (18,19). During the 1990s, this issue has been the focus of much research. On the basis of the resulting evidence, the American Diabetes Association's guidelines now recommend that 60-70 of energy be divided between carbohydrate and monounsaturated fat, depending on patient preference and the appropriate nutritional goals for their medical status (20).

What Are The Potential Adverse Effects Of Highcarbohydrate Diets

During the 1980s and 1990s, a number of controlled intervention studies in healthy individuals who maintained their body weight showed that high-carbohydrate diets often resulted in higher blood TG levels and lower HDL-cholesterol levels - changes that are atherogenic and increase the risk of coronary heart disease - despite improved total and LDL-cholesterol levels (29). These findings sparked particular concern for people with diabetes because their lipid abnormalities tended to be higher TG and lower HDL-cholesterol level rather than the high total and LDL-cholesterol typically observed in non-diabetic individuals (18). Hence the magnified risk of atherosclerosis in people with diabetes might be related to blood lipid risk factors that are specifically worsened by high-carbohydrate diets. The mechanisms by which high-carbohydrate diets decrease HDL-cholesterol are also unknown and should be a priority in future research. In two recent cross-sectional studies of healthy adults, a...

The Scientific Basis For Recommending Highmufa Diets For Diabetes

Many diabetes experts argue in favour of allowing a higher MUFA intake for people with diabetes, on the grounds that high-carbohydrate diets can increase blood glucose, insulin and TG levels and reduce HDL-cholesterol levels. A meta-analysis of nine studies with a total of 133 subjects comparing these two approaches to diet therapy in patients with diabetes revealed that high-MUFA diets (22-33 of energy intake total fat 37-50 energy) improved lipoprotein profiles as well as glycaemic control (19). Compared to high-carbohydrate diets (50-60 energy intake), high-MUFA diets reduced fasting TG and VLDL-cholesterol levels by about 20 and caused a modest increase in HDL-cholesterol (4 ) but had no effect on LDL-cholesterol. There was no evidence that high-MUFA diets induced weight gain in these tightly controlled studies. However, there are several limitations that need to be raised before deciding whether they provide sufficient evidence to formulate recommendations for therapeutic diets

Evidence For Sucrose Restriction In Diabetic Diets

Fructose has also been used as a sweetener in diabetic diets because it has a smaller blood glucose (GI 20) and insulin-raising effect than isocaloric amounts of sucrose. Concerns about its potential to raise TG and LDL-cholesterol levels have limited its use (20), but in amounts up to 12 of energy, no untoward effects have been seen in subjects with diabetes (79).

Calorierestricted Diets

(TG) and high-density lipoprotein (HDL) cholesterol concentrations fell with weight loss, irrespective of macronutrient content, but the decrement in TG concentration was greater, and the fall in HDL cholesterol attenuated, in response to calorie-restricted diets relatively high in MUFA and low in CHO. Low-density lipoprotein (LDL) cholesterol concentration decreased when either MUFA or CHO replaced saturated fat (SF) in the diet, but the improvement in LDL cholesterol concentration did not take place if dietary intake of SF was not decreased. Finally, improvement in all of these variables in response to a diet relatively high in MUFA and lower in CHO persisted several weeks after a period of weight maintenance with the test diets.

Pharmacoeconomics

In a cost-benefit analysis, both costs and consequences are valued in dollars and the ratio of cost to benefit (or more commonly benefit to cost) is computed. Cost-benefit analysis has been used for many years to assess the value of investing in a number of different opportunities, including investments (or expenditure) for health care services. Cost-effectiveness analysis attempts to overcome (or avoid) the difficulties in cost-benefit analysis of valuing health outcomes in dollars by using nonmonetary outcomes such as life-years saved or percentage change in biomarkers like serum cholesterol levels. Cost-minimization analysis is a special case of cost-effectiveness analysis in which the outcomes are considered to be identical or clinically equivalent. In this case, the analysis defaults to selecting the lowest-cost treatment alternative. Cost-utility analysis is another special case of cost-effectiveness analysis in which the value of the outcome is adjusted for differences in...

Variations In Glycaemic Index

Perhaps the best example of the ability of differences in glycaemic index of CHO-enriched diets to modify glycaemic control and lipoprotein metabolism in patients with Type 2 diabetes is the report by Jarvi and colleagues (38). These investigators compared the metabolic effects of two diets, each containing 55 of total calories as CHO, in 20 patients, consuming each of the test diets for 24 days. The glycaemic indices were calculated to vary from 57 to 83 as compared to white wheat bread. The two test diets were compared to each other, as well as to baseline values obtained on an uncontrolled diet. Of considerable interest was the observation that fasting plasma glucose, TG, and LDL cholesterol concentrations fell on both diets, supporting the general belief that essentially any prescribed diet is better than no diet plan. On the other hand, the degree of improvement in all of these variables was the same, irrespective of the difference in glycaemic index of the diet. Furthermore, the...

Estimated Therapeutic and Loael Doses of Garlic

A One may wonder why relatively high doses of DADS are required when oral garlic can reduce cholesterol production in humans at moderate doses. The difference is probably because allicin concentrations in the liver are high after oral administration of garlic, and the liver is the major producer of cholesterol in the body. Allicin is about 10-fold more effective at inhibiting isoprene synthesis than DADS.

Central nervous System symptoms

Coronary heart disease is the leading cause of death in women. Estrogens protect against coronary heart disease by lowering LDL cholesterol and increasing HDL cholesterol concentrations. Estrogen may also provide arterial vasodilation and increased perfusion.

Coronary Heart Disease

Light to moderate alcohol consumption is associated with a similar reduction in CHD risk among diabetic and non-diabetic men and women (27,28). Among the mechanisms accounting for the risk reduction are increased circulating concentrations of HDL cholesterol, inhibition of blood coagulation and the presence of antioxidant substances which reduce oxidative damage (Table 13.2). However, it is also well established that alcohol increases plasma triglyceride. Alcoholic hyperlipaemia results primarily from increased hepatic secretion of VLDL and secondarily from impairment in the removal of triglyceride-rich lipoproteins from the plasma. Raised triglycerides are also a feature of the Increase in total HDL cholesterol metabolic profile of Type 2 diabetes, together with small dense LDL and low concentrations of HDL cholesterol. Hypertriglyceridaemia is an independent risk factor for coronary artery disease especially for people with Type 2 diabetes reduction of alcohol intakes tight...

Physicochemical Interactions and Interactions based on Changes in Local pH and Ionization State of Molecules

A few drugs have structures that readily form chelate complexes with divalent or trivalent cations such as aluminium, magnesium, iron, or calcium. The complexed drugs are not absorbed across the intestine and hence their plasma concentrations may be subtherapeutic. Examples include quinolone antibiotics (e.g., ciprofloxacin) and tetracyclines which are markedly less absorbed when administered together with magnesiumaluminium antacids. Other cations, such as calcium, iron, and probably zinc, appear to interact in a similar manner. Cholestyramine is a basic anion-exchange resin used in the treatment of hypercholesterolemia. The hydrophilic but water insoluble powder is not absorbed in the GI tract, however, it can adsorb bile acids and a number of drugs (e.g., digitalis glycosides, coumarin, diuretics, quinidine, thyroxine, propranolol, and some antibiotics). As a safety precaution it has been recommended to discontinue resin administration for short-term courses of antibiotics,...

What Are Plant Sterols And Stanols

Sitosterol, campesterol, and stigmasterol are 4-desmethylsterols. Their cholesterol lowering effects and the effects of plant stanols have been proven in many trials.3 In contrast, 4,4-dimethylsterols like lupeol, alpha-amyrin, and cycloartenol (Figure 15.2) present in rice bran and shea nut oil hardly lower serum cholesterol.6 The structures of 4-desmethylsterols resemble the structure of cholesterol more than they resemble the structures of 4,4-dimethylsterols. This may be the reason for the difference in cholesterol lowering effect.

Cholesterol Metabolism

Cholesterol is an essential component for the human body. It is one of the building blocks for cell membranes and serves as a precursor for a number of compounds such as steroid hormones and bile acids. Because of the low solubility of cholesterol in the hydrophilic environment of the circulation, it is transported through the blood stream in lipoproteins. A lipoprotein consists of a hydrophilic coat that contains free cholesterol, phospholipids, and apolipoproteins, as well as a hydrophobic core consisting of cholesterol esters and triacylglycerols. Lipoproteins differ in their amounts of cholesterol and triacylglycerol (Table 15.1). The cholesterol the lipoproteins contain is derived from two pathways dietary cholesterol (exogenous route) and endogenous synthesis.

Components and Nutraceutical Characteristics of Soybean

Acids, i.e., healthful oil Mature soybeans are mainly raffinose (0.1-0.9 ) and stachyose (1.4-4.1 ), whose presence is associated with the flatulence produced after human consumption moreover, oligosaccharides are powerfull prebiotics and have been successfully commercialized in Japan for years 12 isomers of daidzein, genistein, and glycitein (aglycones), transformed to daidzin, genistin and glycitin after glucosilation isoflavon content is 1-4 mg g d.w. isoflavones inhibit the growth of cancer cells, lower cholesterol levels, and inhibit bone resorption

Effects of Plant Sterols and Stanols on Serum Lipid and Lipoprotein Concentrations

Plant sterols could not easily be incorporated into food products and intakes of large amounts in the forms of capsules and syrups were necessary to achieve substantial reductions in plasma cholesterol concentrations. Interest in the cholesterol lowering properties of plant sterols decreased until the discovery in the 1970s that esterification of plant sterols facilitated their incorporation into various food products. Since then, many studies have shown that both plant sterol and stanol esters lower serum LDL cholesterol concentrations without effects on serum HDL cholesterol concentrations. In one study of patients with type II diabetes, consumption of plant stanol esters even increased serum HDL cholesterol concentrations by 11 ,16 but this could not be confirmed in another study.17 In recent years, free plant sterols and stanols have been incorporated into food products by improved techniques. Their effects on serum lipoprotein concentrations are the same as those of esterified...

Feedback Regulation of Cellular Lipid Metabolism

As is readily apparent, a cell would soon face a crisis if it did not have enough lipids to make adequate amounts of membranes or had so much cholesterol that large crystals formed and damaged cellular structures. To prevent such disastrous events, cells normally maintain appropriate lipid levels by regulating their supply and utilization of lipids. We have seen how cells acquire lipids by biosynthesis or import and how they export lipids. In this section, we consider the regulation of cellular lipid metabolism, focusing on cholesterol. However, the regulatory pathways that control cellular cholesterol levels also function in controlling fatty acid and phospho-lipid metabolism. Coordinate regulation of the metabolism of these membrane components is necessary to maintain the proper composition of membranes.

Murine Model of Accelerated Atherosclerosis in Mice Infected with a Periodontal Pathogen

Toward that end, our laboratory employed mice deficient in apolipoprotein E (apo E null). In these animals, spontaneous atherosclerosis develops on a normal chow diet driven primarily by hypercholesterolemia. We, and others, have shown that induction of superimposed stresses, such as hyperglycemia or hyperhomocysteinemia, accelerates atherosclerosis in this model. To test the premise that oral infection may accelerate vascular inflammation and macrovascular disease, male apo E null mice were inoculated with the human periodontal pathogen Porphyromonas gingivalis, strain 381, by oral gavage and oral anal topical application, beginning at age 6 weeks. Control animals received vehicle (phosphate buffered saline PBS). In parallel with accelerated alveolar bone loss in infected mice versus those animals receiving PBS, P. gingivalis-infected mice displayed a significant 40 percent increase in atherosclerotic lesion area at the aortic root versus vehicle at age 17 weeks (Figure 1). Although...

A Control of Lipid Metabolism

Diabetic animals exhibit hypertriglyceridemia, hypercholesterolemia, and hyper-phospholipidemia to a very marked extent. A diet rich in fiber and low in fat, particularly saturated fatty acids, is currently recommended for the treatment of non-insulin-dependent diabetes mellitus to achieve better glycemic control and for lowering plasma LDL cholesterol. Interestingly, it has been observed that blood cholesterol is significantly lowered (as much as 29 ) in diabetic animals maintained on a diet containing 0.5 curcumin. The ratio of LDL to very low density lipoprotein (VLDL) decreases by 33 . On the other hand, high-density lipoprotein (HDL)-associated cholesterol is increased 25 by dietary curcumin in diabetic animals. Significant decreases in blood triglycerides and phospholipids (40 and 24 , respectively) have been also brought about in diabetic animals maintained on a curcumin diet. Dietary curcumin also shows a significant countering of renal cholesterol and triglycerides elevation...

Grape Seeds and Red Wine

Tea polyphenols from green and black tea prevented increased serum total cholesterol and triglyceride levels in animals that were fed high-fat, high-cholesterol Cardioprotective effects of flavonoids are complex and include the involvement of homocysteine, cholesterol, platelet function, and the protection of LDL. In a Norwegian cohort study, participants were divided into 5 groups according to levels of tea consumption (less than 1 cup day, 1 to 2 cups day, 3 to 7 cups day, more than 8 cups day, and nondrinkers). Comparing the 4 tea-drinking groups to nondrinkers, plasma cholesterol levels were inversely correlated with tea consumption and serum cholesterol levels decreased by 6, 12, 19, and 28 from the lowest to the highest tea consumption group. Homocysteine levels were affected by tea consumption in these same groups with some different results. Consumers of less than 1 cup day had 6 reductions of plasma homocysteine, moderate consumers of 1 to 2 cups day had 20 reductions, and...

Risk Factors for Impairment of Microvascular Repair

Risk factors for vascular disease, which include diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia, all impair angiogenesis. In turn, this can result in impaired wound healing and complications following surgery. This has been exemplified in bypass graft surgery in the preceding section. Metabolic and dietary factors, can also influence the process. For example, vitamin B6 has been shown to

Cellular Immunity in Atherosclerosis

Cell surface receptor-mediated uptake of various forms of LDLs modulates immune responses via cytokine production (Table 27.2). LDL binding to LDLR on macrophages leads to the production of IL-10, a cytokine known to promote Th2 polarization and humoral immune responses, whereas oxLDL can stimulate the production of IL-12, a proinflammatory Th1 cytokine (Varadhachary et al., 2001). Surface expression of LDLR, however, is negatively regulated by intrac-ellular cholesterol levels. Hence, during atherogenic conditions with increased levels of circulating LDLs, LDLR expression is downregulated once intracellular cholesterol level reaches its threshold. This also decreases LDLR ligation and results in reduced production of IL-10 and a reciprocal increase in IL-12 secretion.

Perspective On Pharmacogenetics In Cardiovascular Medicine

It is clear from the numerous examples reviewed here that genetic polymorphisms can be an important determinant of predicting cardiovascular risk. It is equally clear that these genetic variants determine drug disposition and response in humans. The outcome data with HMGCo-A reductase inhibitors (statins) are particularly interesting in this respect. These studies, conducted in fairly large populations and with specific clinical endpoints (beyond lipid-lowering), focused on the polymorphic genes encoding the proteins, such as APOE, CETP, and stromelysin-1, and showed how the genotype might be associated with worse prognosis.

Garlic and Platelet Aggregation

The effects of garlic and garlic preparations on platelet function have served as the subject of many studies. Rahman and Billington64 studied the effects of dietary supplementation with AGE on 23 adult male subjects for 3 months. These normo-lipidemic subjects consumed 5 ml of AGE daily for 13 weeks. Supplementation with AGE produced no significant changes of serum total, LDL and HDL cholesterol, or serum tryglyceride concentrations. However, AGE supplementation significantly reduced the activity of serum alanine aminotransferase (ALT). ALT is a cytosolic enzyme released into blood as a result of damage to liver cells. Decrease in the activity of this enzyme as a result of consumption of AGE indicates AGE protects hepatocytes against toxins.

Garlic and Cardiovascular Diseases

Ischemic heart disease.74 The consumption of 3 g fresh raw garlic (a single clove daily) by study subjects for 16 weeks resulted in 21 reductions in serum cholesterol levels. This significant reduction was gradual and not observed until 4 weeks into the study. A significant reduction in serum thromboxane levels was also observed.67 Different constituents of garlic have been shown to exert different effects in reducing blood lipid fractions including total cholesterol, LDL cholesterol, and triglycerides. Steroid saponins in garlic were shown to interfere with absorption of cholesterol by the intestinal lumen and lowered plasma cholesterol levels in a variety of experimental animals.75 Matsuura speculates that this may be the result of formation of complexes of saponins and other steroids in garlic products with cholesterol in the intestine, resulting in less cholesterol absorption and lowered plasma cholesterol in experimental animals.76 Ackermann et al.49 described the results of...

Potential Mechanisms Responsible for Deficient Skin Vasodilatation to Mental Stress in Obesity

Obese individuals are known to have increased levels of low-density lipoprotein (LDL) cholesterol and triglycerides and decreased high-density lipoprotein (HDL) cholesterol. In healthy women, skin vasodilatation in response to iontophoresis of acetylcholine, isoprenaline, and nitroprus-side has been shown to be positively correlated to HDL cholesterol, and negatively correlated to the ratio of total cholesterol HDL and triglycerides 4 . Skin postischemic microcirculatory dilatation is blunted in patients with hypertriglyceridemia 17 .

Some additional questions

The choice of target cells is another point worthy of discussion. In some instances, this choice is predetermined, e.g. treatment of the genetic condition, familial hypercholesterolemia, would require insertion of the gene coding for the low-density lipoprotein receptor specifically in hepatocytes.

Toxicity in Either

Androgen administration to male or female adults, especially at high dosages, results in erythrocytosis and polycythemia, fluid retention, and it may produce or exacerbate edema. This can be serious when associated with congestive heart failure, cirrhosis of the liver, or nephrotic syndrome. Since androgens stimulate the activity of sebaceous glands, oily skin and acne are found in some individuals who are receiving androgen therapy. A change in cholesterol levels can result from androgen therapy, such as decreased levels of high-density lipoprotein cholesterol and increased levels of low-density lipoprotein cholesterol. This change in the distribution of cholesterol may contribute to increased risk of atherosclerosis and coronary artery disease, especially in athletes who are exposed for long periods to high levels of anabolic steroids.

The Diseased And Ageing Heart

4.4 Hypercholesterolemia Hypercholesterolemia is a major risk factor for coronary artery disease and the investigation of the response of the myocardium to ischemia and reperfusion in the presence of hypercholesteremia is clinically relevant. This issue though is surrounded by much controversy and factors such as the component of diet, the presence of atherosclerosis, the experimental model of ischemia and reperfusion, and the duration of treatment may account for conflicting reports. The duration of high cholesterol levels appears to be an important determinant of the postischemic outcome. Hypercholesterolemia is associated with larger myocardial infarcts in rabbit hearts subjected to ischemia and reperfusion after short-term cholesterol treatment.209 Similarly, in mice, short-term exposure (2 weeks) to high cholesterol levels does not alter the infarct size in the wild type animal but increases infarct size in animals deficient in the low-density lipoprotein receptor.210 Prolonged...

Dyslipidaemia And Other Cardiovascular Risk Factors

The dyslipidaemia of ESRF is characterised by raised plasma triglycerides with a normal cholesterol level. This form of dyslipidaemia becomes worse after starting CAPD. The lipid profile on CAPD is generally more atherogenic than with other dialysis modalities. A possible contributory factor for this atherogenic lipid profile is the glucose absorption from the dialysates giving rise to enhanced triglyceride synthesis. Chronic hyperinsulinaemia is a major component of the metabolic syndrome and a recognised risk factor for atherosclerosis (36). There is a preferential sieving of the smaller cardio-protective lipoprotein HDL-cholesterol among the proteins lost into the dialysate rather than that of other lipoproteins (37).

And Tumour Like Conditions

Xanthelasmata are yellow papules and plaques, most frequently occurring on the eyelids and the skin surrounding the eyes. They are relatively frequent. Xanthelas-mata can be a manifestation of hypercholesterolaemia, but most cases are idiopathic. Histology shows multiple foamy histiocytes in the superficial dermis (Fig. 10.29).

Other Relevant Polymorphisms

Another example of a disease-related polymorphism that is predictive of drug response involves cholesteryl ester transfer protein (CETP) and pravastatin (HMG-CoA reductase inhibitor used to treat hypercholesterolemia). Kuivenhoven et al. (1998) reported a significant relationship between variation of the CETP gene and the progression of coronary atherosclerosis, independent of lipolytic plasma enzyme activity and plasma HDL cholesterol concentration. If these results are replicated, then the presence of a homozygous polymorphism at this site could be used to predict whether treatment with pravastatin

Evidence for biological determinants of offending behaviour

Genetically mediated, abnormal neurotransmission in the central nervous system of offenders has been explored, principally by Virkkunen in Finland. He found low turnover of brain serotonin in alcoholic violent offenders, together with an abnormality in the gene thought to control serotonin breakdown. (28) Evidence of low cholesterol levels in American army veterans with antisocial personality disorder has been reported, but was not replicated in a Scottish study that found no association between serum cholesterol and aggressive personality traits.(2 30) The significance of these biochemical findings in relation to criminal behaviour is uncertain.

Effects on Other Vasoactive Mediators

Statins inhibit the production of endothelin-1 and the expression of angiotensin receptor I. Beyond their effects on vasomotor tone, these mediators are involved in leukocyte adhesion, thrombosis, and oxidant generation. Adenosine synthesis by EC is enhanced by statins through inhibition of ecto-5'-nucleotidase endocytosis, resulting in increased

Vitamindrug Interactions

Drug interactions and the adverse effects that can result are a special concern. Although vitamins are not always thought of as being drugs, these nutrients can interact with drugs and result in a variety of effects. Vitamin-drug interactions can produce either a decrease or an increase in the effectiveness of the drug conversely, the intake of drugs can affect the disposition of vitamins in the body. Many drugs, such as some laxatives and cholestyramine, can produce vitamin malabsorption or fecal nutritional loss, resulting in drug-induced nutrient depletion and hypovitaminosis. Both fat-soluble and water-soluble vitamins can be affected by drug intake.

Pharmacological Studies in Humans A Primer

The retrospective cross-sectional study is the simplest epidemiological study that can be performed. This study takes a cross-sectional snapshot of data collected from a population, and typically examines the association between a particular medication and the disease (e.g., AD). This type of study provides a rapid, easy assessment of whether there is a positive signal that could be found, but it frequently suffers from false-positive results. Cross-sectional studies are prone to unanticipated factors that can bias the results. For example, a reduced association between a medication and a disease might occur because of prescribing biases. For instance, physicians might exhibit a reduced tendency to prescribe medications that modulate chronic health conditions (e.g., statins or calcium supplements) to subjects with terminal Alzheimer's disease, which could be manifest as a reduced association between the medication and the illness. The experimental design of any epidemiological study...

Pharmacokinetic Considerations

Individual drugs differ in their ability to mediate the various pleiotropic effects of statins. The lipophilic agents (simvastatin, atorvastatin, cerivastatin, fluvastatin, and lovastatin) have prominent effects on VSMC proliferation and contractility, whereas the more hydrophilic pravastatin has minimal effects. A similar difference has been found for certain actions on leukocytes, such as ROS production and inhibition of LFA-1. On the other hand, effects targeting EC have generally been equivalent, when compared. Most studies have employed one of the lipophilic statins, and thus it is not known whether pravastatin would have similar actions. Because of its hydrophilic nature, pravastatin requires a specific organic anion transporter, LST-1, for its uptake into hepatocytes. The distribution of pravastatin to extrahepatic sites is significantly less than the lipophilic compounds. For those actions dependent upon HMG Co-A reductase inhibition, the potency of the various agents will...

Nonsteroidal Antiinflammatory Drugs

NSAIDs have received more attention than statins as a putative medication for treating AD. The rationale for using NSAIDs is cogent because many, many studies document the presence of a strong inflammatory component to the pathophysiology of AD (McGeer & McGeer, 1996). A similar argument also provides support for the use of statins in AD, as described above. Epidemiological studies dating as far back as 1994 show a reduced association between NSAID use and the prevalence or incidence of AD (Breitner et al., 1994, 1995). A recent meta-analysis of these studies suggests that subjects with autoimmune disorders who take high dose anti-inflammatory agents have a modestly lower prevalence of AD (Etminan, Gill, & Samii, 2003). Multiple prospective trials have been performed to test the hypothesis that NSAIDs might reduce the progression of AD. Indomethacin, naproxen, rofexicob, diclofenac misoprostol, and nimesulide have all been examined prospectively (Aisen et al., 2003 Rogers

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