Natural Medicine For High Cholesterol

Beat Cholesterol

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. While IP6 is well known for its cancer-fighting properties, Davis points to its use to lower blood cholesterol. Indeed, the U.S. National Institutes for Health (NIH) actually performed research that actually drew the same conclusion in 1999. IP6 is also known to actually reduce the presence of calcium deposits in arteries, another benefit which will delay or prevent the onset of heart disease. Like all the other Blue Heron Health News promoted health guides, the Beat Cholesterol in 30 Days guidebook will help you achieve better health using an all-natural method. Unlike most prescription drugs, this program ensures a risk-free solution to a reduced cholesterol level in a short span of time. This book will provide you with all there is to know about your silent killer enemy: cholesterol. Read more...

Natural Cholesterol Guide Summary


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My Natural Cholesterol Guide Review

Highly Recommended

I usually find books written on this category hard to understand and full of jargon. But the author was capable of presenting advanced techniques in an extremely easy to understand language.

My opinion on this e-book is, if you do not have this e-book in your collection, your collection is incomplete. I have no regrets for purchasing this.

Ezetimibe and Statins

All of the in vivo data described thus far involve animals fed diets that are substantially higher in fat and cholesterol than the animals' normal chow diet. Despite the substantial activity of ezetimibe and other azetidinone CAIs in these models, none of the compounds tested significantly reduced plasma cholesterol levels in animals fed a normal chow diet. While this was initially a concern, this observation ultimately led to one of the most important aspects of the profile of ezetimibe. In considering the possible reasons for the lack of substantial effect on serum cholesterol in the absence of a high cholesterol diet, Davis reasoned that a CAI might stimulate hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity. This could compensate for a reduced cholesterol load due to inhibition of intestinal cholesterol absorption. If this were the case, then coadministration of a CAI and an HMG-CoA reductase inhibitor should produce an enhanced reduction in serum cholesterol...

A new mechanism to lower plasma cholesterol levels in humans the discovery of ezetimibe at Schering

More recently ezetimibe was discovered at Schering. The drug lowers cholesterol levels in humans by a mechanism that is complementary to that of the statin it blocks intestinal absorption of cholesterol and related phytosterols. The fixed combination of ezetimibe simvastatin, which is marketed as Vytorin, represents a valuable new approach toward optimizing lipid-lowering treatments.

Clinical efficacy of hydroxymethylglutarylcoenzyme A reductase inhibitors statins as lowdensity lipoprotein

Statins represent a class of drugs that specifically inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the rate-controlling step in de novo cholesterol biosynthesis.34 Two general classes of statin have been identified the earlier natural product-based statins (mevastatin 1, lovastatin 2, simvastatin 3, pravastatin 4 Figure 7) and the more recent new generation of synthetic statins (atorvastatin 6, fluvastatin 5, cerivastatin 7, rosuvastatin 8, pitavastatin 9 Figure 7). Since their initial discovery in the mid-1970s, multiple statins have been

Combinations of statins and cholesterol absorption inhibitors

The complementary nature of the two inhibitory mechanisms targeting HMG-CoA reductase and cholesterol absorption suggests that combinations of these agents may have additive or perhaps even synergistic clinical benefits. The first clinical evidence supporting this hypothesis was observed from the additional lipid lowering that could be achieved by using ezetimibe as an add-on therapy to patients who are already taking statins. In this study, 10 mg ezetimibe was given to patients on stable simvastatin therapy. The addition of 10 mg ezetimibe produced an additional 25 reduction in LDLc, indicating a significant synergistic effect.53 In another trial, the addition of 10 mg of ezetimibe to 10 mg atorvastatin achieved 50 reduction in LDLc, comparable to that seen with an 80 mg dose of atorvastatin alone. Thus, combinations of statins with ezetimibe offer the opportunity to lower significantly the statin dose needed to achieve lipid targets, perhaps with potentially increased safety.

Antioxidants in combination therapy with statins

Several clinical studies have examined antioxidants in combination with various statins. However, no significant beneficial effects in coronary event reduction were achieved by adding vitamin E to simvastatin, pravastatin, or atorvastatin. Notably, in the secondary prevention HDL Atherosclerosis Treatment (HATS) trial, treatments with antioxidants such as vitamin E, vitamin C, and beta-carotene were compared alone or in joint therapy with a combination of simvastatin 3 and niacin 17. In contrast to the lipid-lowering effects and reduction in coronary events observed with the simvastatin niacin combination alone, antioxidants by themselves demonstrated no significant benefit in disease progression and coronary outcomes. However, the beneficial effects of simvastatin niacin on lipid lowering and disease progression were essentially negated when this combination was administered together with antioxidants. Thus, supplementation with antioxidants produced a significant negative outcome...

Combinations of statins with highdensity lipoprotein cholesterolelevating agents

While statin therapy offers a significant therapeutic benefit to the subset of patients that respond to these agents, typically, more than 60 of the statin-treated patients in controlled trials continued to develop cardiovascular disease and failed to experience a therapeutic benefit.34 Most of these nonresponders also had low HDLc levels. Since statins produce only modest increase of HDLc ( 10 ),34 several studies have been conducted to define the potential benefit using statins in combinations with either fibrates or niacin. For example, in the HATS secondary prevention trial, CHD patients with low HDLc (

Limitations of Low Density Lipoprotein Cholesterol Reduction and Statin Therapy

A clear overall therapeutic benefit has been achieved by lowering LDLc with multiple statins in a subset of patients with established CHD and in primary prevention for high-risk patients. Based upon these positive benefits, statin use has increased such that recent population studies now indicate that in 2002 over 9 of the US adult population were taking some form of statin.77 However, even in controlled clinical settings, the majority of patients fail to reach their projected lipid levels and significant numbers of patients fail to achieve a therapeutic benefit as they continue to experience major coronary events while continuing statin treatment. While coronary event reductions of 25-30 are observed with statins as monotherapy, in secondary prevention trials, nearly 70 of the patients have coronary events that are not avoided. Thus, the search has continued for alternative strategies to lower LDLc or to increase the clinical effectiveness of statins using combination therapies. In...

Medications for High Cholesterol

Sometimes, despite making changes to their diet, some people continue to have excessive serum cholesterol concentrations. This situation occurs in patients with the nephrotic syndrome, and in those diabetics who have relatively high rates of protein excretion. These high serum cholesterol levels usually can be treated readily in patients with and without renal failure, including people with diabetes, by the administration of a statin drug. These drugs are just as effective in renal disease as in its absence, and no more toxic. They are being used more and more widely, and seem to have other beneficial effects some may reduce the incidence of Alzheimer's disease, and some may reduce the incidence of osteoporosis. Also, muscle damage can occur from statins and can lead to the release into the blood of a protein from damaged muscle, myoglobin, that can cause the kidneys to shut down entirely. This form of acute renal failure has caused the deaths of a number of patients and recently has...

Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors Statins

Statins specifically target and potently inhibit HMG-CoA reductase, the enzyme that catalyzes mevalonate formation and represents the rate-controlling step in de novo cholesterol biosynthesis (Figure 7).34 No toxic metabolites accumulate as a result of the inhibition of HMG-CoA reductase. HMG is water-soluble and has a number of metabolic pathways available to preclude buildup of this intermediate. However, in vivo, the resulting decrease in mevalonate that occurs from inhibition of HMG-CoA reductase reduces the overall concentration of the steroid pool. In response to this depletion, HMG-CoA reductase expression increases and the hepatic LDLr is upregulated. Approved statins (Figure 7) consist of two subclasses the early first-generation natural product-derived or their related semisynthetic analogs (mevastatin 1, lovastatin 2, simvastatin 3, pravastatin 4), and the newer second- and third-generation synthetic analogs containing a central core aromatic heterocycle (atorvastatin 6,...

Safety concerns with statins

Data from animal studies have indicated that pronounced inhibition of cholesterol biosynthesis with high doses of statins induced multiple toxic side effects, including liver enzyme elevations, cataracts, skeletal muscle changes, central nervous system lesions, and certain tumors. However, overall, good safety and tolerability have been observed for the first- and second-generation statins in multiyear clinical trials, and millions of patients have been safely treated with approved doses of these agents. Withdrawals due to adverse events from statins in several multiyear trials were similar to placebo, and the overall incidence of clinically significant adverse events has been quite low. Initial concerns about cataract formation are no longer considered a significant safety issue since several clinical studies monitoring optical lens opacity with the early statins showed that these occurred at the same rate in both statin-treated and placebo groups. Since statins target cholesterol...


HMG-CoA reductase inhibitors, the so-called statins, are currently being tested in clinical trials for their efficacy as MS therapeutics,34 and for their ability to reduce cholesterol in adolescents with SLE (see Figure 1 and Table 2). Beyond their cholesterol-reducing properties, statins have pleiotropic effects - including anti-inflammatory and neuroprotec-tive properties. In preclinical studies, statins inhibited the onset and progression of disease in EAE by inducing a shift from Th1 (proinflammatory) toward Th2 (anti-inflammatory) cytokine production. In vitro studies suggest that statins inhibit lymphocyte migration across the blood-brain barrier. Further, statins may promote remyelination. In an open-label study of 30 RRMS patients, a simvastatin regimen decreased lesional activity assessed by MRI, and was well tolerated however, it did not affect EDSS scores or yearly relapse rates.35 Statins have many advantages beside being well tolerated, they are administered orally, have...

Functional Anatomy of Brown Adipose Tissue

All this allows for a fast and highly regulated transformation of the potential energy contained in triglycerides into heat, also accounting for brown adipocyte anatomy given the enormous demand for oxidisable substrate (the lipid vacuoles), and that lipolysis can take place only on the surface of the vacuoles, a multilocular organisation is essential to increase the contact surface between lipids and hyaloplasm. Such ready substrate availability would be useless without a large number of mitochondria - which large size and abundance of cristae make very efficient - ready to carry out the oxidation process.

Validating intermediate endpoints or surrogates

For cholesterol to be an effective IE S, the cholesterol effect in this regression should be clinically and statistically significant. If the treatment effect is large, this indicates that the cholesterol-lowering drug alters the chance of acquiring CAD independently of cholesterol levels. Thus, cholesterol levels will not accurately predict the chance of CAD and it is likely to be an imperfect surrogate. Similarly, if there is a significant treatment X cholesterol interaction, this indicates that the treatment alters the chance of acquiring CAD differently for patients with different cholesterol levels. Again, it is more difficult to predict changes in CAD incidence based on changes in cholesterol and this relationship will depend on the cholesterol profile of the sample under study. In order to quantify the extent to which an IE S is useful, we can estimate the proportion of the E I effect which is explained by the IE S from the attributable fraction (AF). In our example, AF is the...

The In Vivo Activity of SCH 48461

The effect of SCH 48461 in cholesterol-fed rhesus monkeys is summarized, along with control animals, in Figure 3. The total serum cholesterol level in the control animals steadily increased over a period of 3 weeks compared with the monkeys dosed with SCH 48461 at 1 mgkg_ 1 over the course of the same period. The serum cholesterol levels did not show any significant change in the SCH 48461 group, and remained at the baseline. At the end of 3 weeks the control animals were administered SCH 48461 at 1 mgkg_ and it was observed that their cholesterol levels returned back to the baseline in a short period of time. The withdrawal of SCH 48461 from the second group of monkeys resulted in the rise of their serum cholesterol levels, again in a very short period of time. These results unequivocally established that SCH 48461 is a potent inhibitor of cholesterol absorption in various species of animals, and, based on its lack of ACAT inhibitory activity, it was obvious that SCH 48461 inhibited...

Discovery of the Prototype Azetidinone Cholesterol Absorption Inhibitor

The discovery program that led to ezetimibe began as a traditional drug discovery program to discover novel acyl-coenzyme A cholesterol acyltransferase (ACAT) inhibitors.14 Although ACATwas known to be involved in a variety of cholesterol trafficking events including cholesterol absorption in rodents, the relevance of ACAT in nonrodent species was still unclear at the time this program began. Nonetheless, a variety of structural classes were known to be potent ACAT inhibitors in vitro and to be active in rodent animal models that reflect a potential for lowering cholesterol levels. Among these models was the cholesterol-fed hamster.15 A high-cholesterol diet dramatically increases liver cholesteryl ester (CE) levels in these animals, making them especially sensitive to ACAT inhibition. By contrast, serum cholesterol (SC) levels are not dramatically changed by cholesterol feeding in these animals, and most ACAT inhibitors have minimal effect on serum cholesterol levels. Figure 1 shows...

Apolipoprotein E Expression in the Adult Brain of Mammals

In the vascular compartment, apoE is found in association with several classes of lipoproteins including chylomicrons, the very low-density lipoprotein (VLDL), and a subclass of the HDL.70 These apoE-containing lipoprotein complexes carry lipids such as cholesterol, cholesterol esters, phospholipids, and triglycerides. Apolipoprotein E serves as a ligand for several cell surface receptors that mediate lipoprotein uptake, and thus apoE participates in lipoprotein metabolism and lipid homeostasis. All known receptors for apoE have been shown to be present in the mammalian brain on one or several cell types, including neurons (for a review, see 71). These receptors are members of a single family and include the low-density lipoprotein (LDL) receptor, the very low-density (VLDL) receptor, the apoER2 receptor, the LDL receptor-related protein (LRP), and the gp330 megalin receptor.

Quantification of coronary atherosclerosis for cardiovascular risk assessment the hole in the doughnut

It is remarkable that two investigators, Crawford and Levene, already described the complexity of coronary pathology in 1953 (Paper no. 1). Based on the observations of pressure-distended and undistended aortic wall specimens, the authors stated that ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media, which may bulge outwards . Not surprisingly, these post-mortem observations did not find widespread clinical attention, because in vivo imaging of coronary arteries to confirm clinical significance, was not possible. A few years later, in the late 1950s, selective coronary angiography was the first imaging modality introduced to clinical cardiology. As described in the paper by Proudfit, Shirey, and Sones (Paper no. 2), the diagnosis of coronary disease in the pre-angiographical era relied solely on the elucidation of historical or clinical symptoms of ischaemia. The correlation of these ischaemic syndromes with angiographical findings...

Use in Prevention and Therapy

Vitamin B6 has multiple beneficial actions in the prevention and treatment of coronary heart disease and peripheral vascular disease. It reduces the tendency for platelets to clump together, lowers LDL cholesterol and raises HDL cholesterol, and reduces levels of blood homocysteine.8,9

A breakthrough at Sankyo the discovery of compactin

As Dr Jonathan Tobert pointed out, ''early attempts to reduce cholesterol biosynthesis were disastrous.''61 In the 1960s triparenol, also known as MER-29, entered clinical trial as an inhibitor of cholesterol biosynthesis. The complex biosynthetic pathway leading to cholesterol is well understood. It is a process involving more than 30 enzyme-catalyzed steps. Unfortunately, triparenol inhibits that process at a late step and thus leads to the irreversible accumulation of desmosterol which is more harmful than cholesterol. It thus became clear that any drug that would safely inhibit cholesterol biosynthesis should block an early step in the pathway and one that does not result in the build-up of an intermediate. The enzyme b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase catalyzes the rate-limiting step in the conversion of HMG-CoA into mevalonate. Therefore, it appeared an attractive target for inhibition, since its inhibitors would be expected to be devoid of any mechanism-based...

Relation of arterial geometry to luminal narrowing and histological markers for plaque vulnerability the remodeling

Matsuzaki M, Hiramori K, Imaizumi T, et al. Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol 2002 40 220-227.

The discovery of the first approved phydroxypmethylglutarylCoA reductase inhibitor lovastatin

Fortunately, Merck was in an excellent position to respond quickly and effectively to the reports from Sankyo that compactin is effective in lowering LDL-cholesterol levels in humans. This was due in part to the fact that, as mentioned above, the head of Research at the time, Dr P. Roy Vagelos, an authority in lipid metabolism and Mr Alfred W Alberts, a long-time associate of Dr Vagelos, had both moved from Washington University in St. Louis to Rahway, providing critically important expertise. Equally important proved to be the fact that Dr Arthur A. Patchett had initiated a fermentation product for screening project (FERPS) at Merck in 1974 to supply microbial extracts for both in vitro and in vivo screens.68 Indeed, in 1978 that program achieved a major breakthrough very quickly, leading to isolation of lovastatin (then called mevinolin). Initial concerns that Merck's HMG-CoA reductase inhibitor might be Endo's compactin were laid to rest when it was shown to differ from Sankyo's...

Lipoatrophy Associated with Multiple Symmetric Lipomatosis Launois Bensaude Syndrome or Madelung Collar

Pharyngeal accumulation of fat tissue. In some 20 of MSL patients, fat infiltration of the pha-ryngeal and tracheal wall was found to be responsible for an obstructive apnoea syndrome during sleep. Metabolic abnormalities include hyper-triglyceridaemia and high levels of circulating HDL cholesterol. Hyperuricaemia and reduced glucose tolerance or overt diabetes occur at a frequency slightly higher than casually expected. A defect in adrenergic-stimulated lipolysis 50 and an increase in lipoprotein lipase activity of adipose tissue 51 have been demonstrated in samples of lipomatous tissue. No information is available on the metabolic activity in uninvolved subcutaneous adipose tissue, due to the fat atrophy which makes fat sampling extremely difficult.

Proinflammatory Cytokines

TNF-a has been shown to promote lipolysis and inhibit lipogenesis and plays a key role in the depletion of adipose tissue mass seen in cachexia. It has been proposed that an elevation in plasma levels of TNF-a is responsible for the metabolic alterations in adipose tissue seen in cachexia 24 . Lipid metabolism is a complex sequence of events that determine whether the triglyceride pool within the adipocyte increases, due to the processes of free fatty acid (FFA) uptake and lipo-genesis, or decreases, due to the process of lipoly-sis. Circulating lipoproteins and triglycerides are first converted into FFA by the action of lipopro-tein lipase (LPL), which is secreted by the adipocyte. FFA can then enter the adipocyte via a fatty acid transporter. Once inside the adipocyte, the FFA is converted into the triglyceride by a multi-step-regulated enzymatic reaction, one of the enzymes involved being acyl-CoA synthetase. In addition, triglyceride can be formed from the uptake of glucose, via...

Raloxifene and Lipids

Estrogen increases HDL cholesterol levels and decreases LDL cholesterol levels in humans39,171 as well in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor.172 In ovariectomized rats, raloxifene treatment has been shown to reduce serum total cholesterol concentrations,97,173 and this reduction correlates with the extent of raloxifene binding to the estrogen receptor.97,173 These results are not surprising for a 'nonsteroidal antiestrogen,' as the original observations for clomiphene analogs and tamoxifen show (see 8.08 Tamoxifen). Raloxifene may also have cardioprotective effects because of its antioxidant properties. This is important since oxidative modifications of LDL have been implicated in atherogenesisis.174 Raloxifene also appears to have a favorable effect on lipid parameters in postmenopausal women. In the published European trial,78 treatment with raloxifene in a dosage of 30, 60, or 150 mg day_ 1...

Biomedical Background

Medieval physicians first observed lipoproteins (milky serum) in association with diabetes mellitus, nephrotic syndrome, and overindulgence of alcohol. In the early 1900s studies focused on the metabolism of plasma cholesterol and triglycerides. This approach quickly gave way to the study of the various lipoprotein classes after it was recognized that lipids and cholesterol were merely cargo and that apolipoproteins on the surface of lipo-protein particles were involved in their metabolism. All of the major lipoprotein particles consist of a shell of amphipathic proteins (apolipoproteins), unesterified cholesterol and phospholipids (hydrophilic on one face and hydrophobic on the other), and a core of triglycerides and cholesterol esters. However, the concentration and characteristics of these particles differ as shown in Table 1. They are classified according to increasing density chylomicrons (

Antiinflammatory compounds Statins Dietary cholesterol affects the formation of Ab and accelerates the appearance of AD pathology in mouse models high serum cholesterol and low high-density lipoprotein cholesterol levels are AD risk factors.57 Cholesterol-lowering agents, e.g., statins, are of interest as treatments for AD. These agents inhibit b-hydroxy-b-methyl glutaryl-CoA reductase, a key regulatory enzyme in the cholesterol biosynthetic pathway. Atorvastatin 49, evaluated in an intention-to-treat clinical trial, showed positive benefit in ADAS-cog performance at 6 months.58 An observational study of AD patients treated with lipid-lowering agents, 47 of which were statins, showed a positive benefit (i.e., slower decline) on the MMSE.59 Thus, with further study statins may become standard therapy.

Other Selective Estrogen Receptor Modulators

Current interest in new SERM molecules has built on the experience of the prototypes with the goal of enhancing bioavailability and selectivity and decreasing side effects (i.e., breast cancer, uterine cancer, and blood clots). All compounds under study have predominantly antiestrogenic effects in the rodent uterus with virtually no estrogen agonist properties. In order to improve upon the raloxifene pharmacophore, some groups have reported on the effect of modifying the benzothiophene nucleus. Particularly noteworthy were two discoveries made by the chemists at Eli Lilly which improved upon raloxifene.77 One change involved the introduction of a methyl ether on either the 5-OH or the 4'OH position, which resulted in compounds with increased potency in a cholesterol reduction assay in ovariectomized rats.178'179 The other change involved the replacement of the carbonyl 'hinge' with other atoms or groups, including N, CH2, S, and O. The change to the oxygen atom resulted in a compound...

Conventional Lipoprotein Analyses

After visual observation of the specimen, the next most useful and reliable tests are determinations of triglyceride and total cholesterol concentrations. These are used as a decision point for the logical progression in the evaluation of a patient suspected of having an abnormality of plasma lip-ids. However, triglyceride and cholesterol values alone do not address the equally important lipoprotein deficiency states (e.g., decreased HDL levels). It also carries the uncertainty that the atherosclerotic risk will be overestimated in patients with a high cholesterol because of a high HDL cholesterol. Routine lipoprotein profile consists of measurement of serum cholesterol, triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C). This is supplemented in special clinical settings by Lp(a), Apo A-I, and Apo B-100 determination. The routine procedure for lipoprotein quantification is to determine HDL-C in the supernatant after precipitation of apolipoprotein-B-containing...

Introduction and Historical Overview

Interest in the posttranslational modification of proteins by prenylation grew out of studies in the early 1980s, which sought to understand how cholesterol-lowering statin HMGCoA reductase inhibitors blocked cell proliferation in vitro 1,2 . The growth arrest was not due to cholesterol depletion, since neither exogenous cholesterol nor cholesterol intermediates could reverse the effects. Only mevalonic acid reversed the effects of HMGCoA reductase inhibitors. By tracking the fate of radiolabeled mevalonate in cells treated with HMGCoA reductase inhibitors, the presence of proteins covalently labeled with the radiotracer revealed a novel mechanism for the posttranslational modification of proteins involving an isoprenoid intermediate of cholesterol synthesis (Fig. 1) 3 .

Triglyceride Total Protein and Live Weight Determination

Virgin males and virgin females were randomly collected from the vials and bottles and prepared as described previously in the Materials section to control for density. Six replicates per line per sex, each containing a pool of 10 flies, were used for the experiment. Twenty-four hours after collection, flies were weighed and homogenized. The homogenization protocol is the same as in Clark and Keith (68). Briefly, adults were homogenized on ice using 25 pL of homogenization buffer (discussed previously). The homogenates were cen-trifuged in a microcentrifuge at 2000 rpm for 2 min. The lipid layer on the surface was resuspended with the supernatant and the homogenate were distributed in 0.5 mL tubes. Live weight, triglycerides, and total proteins were measured for each sample, following the protocols listed as follows 2. Triglycerides were assayed spectrophotometrically using the Vitros DT60 II reader (Johnson and Johnson Clinical Diagnostics, Inc.) and Vitros TRIG DT slides. The Vitros...

Statistical Analyses for Triglyceride Total Protein and Live Weight

For all three assays, analysis of covariance (ANCOVA) was used to detect genetic phenotypic variation due to food source and gender, with body weight and total proteins as covariates. The results of feeding flies for 10 d in the control, palmitic acid, soy, and beef diets are shown in Table 1. The seven dietary conditions used in this chapter and when the assays were performed are summarized in Fig. 1. The significant results (i.e., p 0.05) of these metabolic experiments were that triglycerides were significantly lowered in female flies and pooled male and female flies after 10 d on the beef diet (p 0.0233 and p 0.0075, respectively). Also, the total protein significantly increased almost two-fold in male flies fed soy for 10 d (p 0.0132) and significantly increased by more than 50 in pooled flies fed beef for 10 d (p 0.001). None of the other conditions produced significant effects in triglyceride levels or total proteins, and none of the three diets significantly affected live...

David M Holtzman Mary Jo LaDu and Anne M Fagan

The intercellular transport of lipids through the aqueous circulatory system as well as within tissues and other body fluids requires the packaging of these hydrophobic molecules into water soluble carriers (lipoproteins) and their regulated targeting to appropriate tissues by receptor-mediated endocytic pathways as well as scavenger receptor-mediated pathways.1 Lipoproteins have been classified into several major groups on the basis of the density at which they float by ultracentrifugation. In the plasma, chylomicrons and very low density lipoproteins (VLDL) are large particles that have a high lipid to protein ratio and are the major carriers of triglycerides. Intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) are intermediate sized particles that are high in cholesterol and cholesteryl esters in humans, LDL are the principal cholesterol transporting lipoproteins in the plasma. High density lipoproteins (HDL) are the smallest particles and contain the highest...

Insulin and Diabetes Mellitus

Energy is constantly required in human life, whereas it is supplied only by intermittent food intake. Therefore, food is usually ingested in excess of the immediate caloric needs, and the extra calories are stored in the form of hepatic and muscle glycogen, adipose tissue triglycerides, and to a certain extent as muscle protein. In turn, these fuel reservoirs are broken down during starvation to provide energy for the body. The amount of glycogen stored in skeletal muscle is about 400 g (1600 Kcal), the amount of glycogen in liver is about 75 g (300 Kcal), and the amount of triglycerides stored in adipose tissue is about 15 000 g (141 000 Kcal), at overnight fasting state in healthy men. Glucose and free fatty acids, which are stored as glycogen and triglycerides, respectively, are the two principal circulating fuels in humans. Endogenous glucose is produced by gluconeogen-esis in the liver and glycogenolysis not in skeletal muscle but in the liver 1 . Energy reservoirs in humans are...

Lipodystrophic Syndrome

In patients with various types of lipodystrophy and in several animal models. Since the extent of fat loss determines the severity of the complications, a common mechanism seems likely. Only limited quantities of triglycerides can be stored in unaffected fat depots in patients with marked fat loss. Excess triglycerides may then accumulate in the liver and skeletal muscles, contributing to insulin resistance. Although hyperinsulinaemia may initially compensate for insulin resistance and maintain euglycaemia, gradual progression of beta-cell dysfunction can lead to overt hypergly-caemia 35 .

Experimental Models of Caloric Restriction and Applicability to Humans

More controlled studies of CR are ongoing using nonhuman primates, mostly Rhesus monkeys. Given the phylogenetic proximity between Rhesus monkeys and humans, these studies will shed some light on the question of CR relevance to man. Data from the primate studies have been reviewed elsewhere (5) and will not be discussed in detail here. Briefly, monkeys on CR exhibit many physiological responses consistent with those observed in rodents such as reductions in body weight and adiposity, fasting glucose and insulin, body temperature, and changes in serum lipids (e.g., cholesterol and triglycerides), among others (see Table 1). Emerging data suggest that CR may also favorably impact age-related diseases and associated morbidity and perhaps even mortality (5,6). Systolic blood pressure Heart rate Serum triglycerides Serum HDL2B

Nutritional Recommendations for Cancer Patients

If, for an extended period, adequate food intake is no longer possible, dietary drink mixes and supplements may be added to the diet. (An energy intake of less than 1200kcal day no longer guarantees adequate intake of essential nutrients.) Individual needs of the patient can be addressed by a special composition of the diet (rich in energy and proteins, with or without fiber, with fats containing medium-chain triglycerides, without lactose). Formula diets are well suited, especially for patients who live on their own and, due to their disease, may not have the possibility, energy, or desire to cook a meal adjusted to their individual needs (77).

Clinical Outcome and Reverse Epidemiology

Many recent studies have suggested that protein-energy malnutrition and inflammation in maintenance dialysis patients are associated with a decreased quality of life and increased hospitalisation and mortality, especially from cardiovascular diseases 10,27,28,123 . Epidemiological studies indicate that hypoalbuminaemia and increased serum CRP are strong predictors of poor clinical outcome in the CKD population 36, 37 . Compared to traditional risk factors, such as obesity, hypercholesterolaemia, and hypertension, hypoalbuminaemia per se, which is generally considered an indicator of MICS, has one of the most striking and consistent associations with the prediction of clinical outcome in these individuals 146 . In highly industrialised, affluent countries, protein-energy malnutrition is an uncommon cause of poor outcome in the general population, whereas over-nutrition is associated with a greater risk of cardiovascular disease and has an immense epidemiological impact on the burden of...

Perturbation of metabolic flux control the role of substrate overabundance

It is well known that increased circulating triglycerides and FFA are frequently associated with pathophysiology of insulin resistance and diabetes mellitus. Searching for the mechanism of their action on glucose metabolism, Sir Randle et al. (1963) observed that elevated circulating free fatty acids (FFA) impair skeletal muscle glucose uptake. The results of his studies allowed him to postulate the hypothesis that substrate competition for mitochondrial oxidation is the major mechanism involved in this action. According to this hypothesis, experimental challenge by FFA would first increase the intracellular glucose-6-phosphate

Definition of Metabolic Syndrome

MetS is a commonly occurring cluster of clinical phenotypes that are individually and collectively strongly related to cardiovascular disease.2 MetS is characterized by disturbed carbohydrate and insulin metabolism, and is clinically defined by threshold values applied to indices of central obesity, dysglycemia, dyslipidemia, and or elevated blood pressure, which must be present concurrently in any one of a variety of combinations.2'3 The cardinal feature of MetS is abdominal obesity, as quantified most directly by increased waist circumference.4,5 Biochemically, MetS is characterized by insulin resistance - hyperinsulinemia - and by dyslipidemia - most typically raised triglycerides and or reduced HDL cholesterol. Additionally, a range of biochemical abnormalities have been secondarily associated, including increased serum concentrations of apolipoprotein B, fibrinogen, free fatty acids, C-reactive protein (CRP), tumor necrosis factor (TNF)-a, interleukin-6, and plasminogen activator...

Genes and the Metabolic Syndrome Complex Trait Genetics

For instance, in certain North American aboriginal communities, such as the Oji-Cree of Ontario, the combined prevalence of impaired glucose tolerance and type 2 diabetes is approximately 40 .40 This development has been inextricably linked with the recent doubling of hospitalizations for coronary heart disease among Oji-Cree, despite declining rates in the general Canadian population.41 Among Oji-Cree adults aged 35 and older, 43 had MetS.42 Furthermore, 8.7 of female Oji-Cree adolescents had MetS, as defined by the NCEP Adult Treatment Panel (ATP) III47 criteria. Increased waist girth and depressed HDL cholesterol were the most prevalent individual components in subjects with MetS. Common functional polymorphisms in genes encoding proteins involved in the renin angiotensin system, the G-protein family (GNB3) and components of triglyceride-rich lipoproteins were each significantly associated with MetS in Oji-Cree adults, especially women.43 Such studies suggest that...

Insights into Metabolic Syndrome Progression from the Monogenic Disorders

Nondiabetic FPLD2 subjects have high plasma insulin, triglycerides, free fatty acids, and CRP, together with low plasma HDL cholesterol and adiponectin long before diabetes developed.43 Thus, the characteristic cluster of biochemical abnormalities precedes the relatively late decompensation of glycemic control among carriers predisposed to lipodystrophy. A similar pattern of progression - i.e., early hyperinsulinemia with dyslipidemia and altered adipocytokines followed by hypertension and finally diabetes - may be important in 'garden-variety' MetS. In both cases, spillover of FFA from adipose tissue and uptake and storage viscerally and in ectopic sites, such as muscle and liver, may be a key inciting pathophysiological event. In FPLD, spillover of free fatty acids occurs because there is an anatomical absence of the peripheral subcutaneous fat buffer. In 'garden-variety' MetS, this spillover occurs because peripheral fat stores become saturated. If this pattern of metabolic...

Modulation of Pain by the Hypothalamic PituitaryAdrenal Axis

During stress, the increased secretion of CRH and arginine vasopressin (AVP) into the hypophysial-portal system of the anterior pituitary enhances the synthesis and release of ACTH (Fig. 4), which can be demonstrated in both the cerebrospinal fluid and blood (74,75). Elevated ACTH content in blood, in turn, increases the synthesis and release of adrenal glucocorticoids, which act in synergy with catecholamines to produce lipolysis, glycoge-nolysis, and protein catabolism, resulting in increased blood glucose content, essentially providing a readily available energy source to aid in the stress response. The delivery of energy substrates is enhanced by increased blood flow as a result of glucocorticoid- and catecholamine-induced increases in cardiovascular tone. Prolonged exposure to elevated stress hormones, however, can present a risk. Glucocorticoids and catecholamines promote the suppression of anabolic processes, muscle atrophy, decreased sensitivity to insulin, and a risk of...

Diagnosing Osteoporosis

The 1993 definition emphasized that both mass and architecture contributed to bone strength. The presence of a fracture was not required before a diagnosis of osteoporosis was appropriate. Fracture, as an outcome of skeletal fragility, was separated from the disease, osteoporosis. This was similar to the approach taken with hypertension and hypercholesterolemia. Hypertension reflects the measurement of a quantity, the blood pressure, which has reached a level that places the individual at risk for the undesirable outcome of stroke. Hypercholesterolemia refers to the measurement of a quantity, cholesterol, which has reached a level that places the individual at risk for the undesirable outcome of myocardial infarction. In both cases, the occurrence of the outcome is not required before the diagnosis of disease is made. In a strict sense, hypertension and hypercholesterolemia are not diseases in and of themselves. They are risk factors for the undesirable outcomes of stroke and...

Guidelines of the study group of the who for the diagnosis of osteoporosis

Factors for fracture as well as being used as criteria for the diagnosis of disease but that these two uses of the values were really quite distinct. The study group noted the analogy to hypertension and hypercholesterolemia described above. Although no other authoritative body has published proposed diagnostic levels of bone density for osteoporosis, a slightly higher cut-off level has been equated with the diagnosis of osteoporosis in the United States. In approving certain medications for the management or treatment of osteoporosis, the US FDA has recommended the use of these drugs in individuals with a bone density that is more than 2 SD below that of the young adult. In essence, this equates a diagnosis of osteoporosis with a bone density that is more than 2 SD below that of the young adult, in contrast to the lower cut-off proposed by the WHO of 2.5 SD or more below that of the young adult.

Benefits of Glycemic Control

The DCCTand UKPDS demonstrated the benefits of glycemic control on the prevention of diabetic microvascular complications and potential benefit in diabetes-associated CVD. Independently, diabetes is a risk factor for CVD morbidity and mortality equivalent to having pre-existing coronary artery disease. Therefore, the treatment goals for modifiable cardiac risk factors, specifically blood pressure and abnormal lipid levels, are more aggressive in individuals with diabetes55 (Table 5). The ADA recommends a goal blood pressure of 130 80 mmHg, LDL cholesterol of 50 mgdL_ 1 in women), and triglycerides

Biochemical Phases of Cachexia

In the normal fast, hypoglycaemia stimulates the production of glucagon, which induces glycogenolysis in the liver and in the muscle to produce glucose. But if glycogen stores can supply glucose only for 12-18 h, then hypoglycaemia stimulates the production of epinephrine, which in turn starts lipolysis in fat stores. About 160 g fat (triglycerides, FFA, glycerol) day can be transformed into glucose to maintain vital processes. But, if the requirement for energy is prolonged,

AGlucosidase inhibitors

When used as monotherapy, acarbose and miglitol are not associated with hypoglycemia or significant weight changes. Blocking the absorption of complex carbohydrates decreases the caloric uptake of the small intestine, but the large intestine compensates to assure that adequate caloric goals are met. a-Glucosidase inhibitors do not significantly affect LDL or HDL cholesterol concentrations, but triglyceride levels decline. These agents may prove to be useful in the management of severe hypertriglyceridemia in both the diabetic and non-diabetic population.

Futile Metabolic Cycles of Lipids

Hypertriglyceridaemia starts mainly through the inhibition of LPL, which regulates the clearance of plasma triglycerides (Fig. 8) and energy production from lipids (Table 4). The increase in plasma triglycerides observed in cachexia is due not only to LPL inhibition and clearance, but also to increased VLDL synthesis from free fatty acids (FFA), resulting from the lipolysis of peripheral fat 78 . By blocking lipoly-sis in the fat cell, for example with phenyl-isopropyl-adenosine, FFA and plasma triglycerides can be reduced 83, 89 . This indicates that liver synthesis of VLDL starts from FFA mobilised from peripheral fat, re-esterified to triglycerides by the liver, and secreted as VLDL 78 - a typical exam- ple of the energy-wasting 'futile' metabolic cycle (Fig. 9). Fatty acids mobilised from peripheral fat reach the liver, where they escape oxidation, are then re-esterified to triglycerides, and pass into blood circulation as VLDL. These lipoproteins return in the adipose tissue to...

Crp Determination Beyond Risk Prediction

CRP levels predict the risk of adverse cardiac events, but it is unclear whether they can guide the management of patients in ACS. This issue has not been explored by any controlled randomized trials, but some suggestions come from retrospective analysis. As described, patients with low hs-CRP and troponin levels have a very favorable prognosis. Mortality among these patients is extremely low and therefore the assumption of a lesser need for aggressive therapy in this group appears reasonable. Targeting of drug therapy on the basis of CRP levels was shown to be effective in a primary prevention trial (45). Interestingly, medical therapy known to be effective in the treatment of ACS (i.e., aspirin 46 , clopidogrel 47 , abciximab 48,49 , and statins 50 ) appears to lower cardiac risk together with CRP levels. Controlled, prospective studies are needed to define better the role of hs-CRP as a guide to therapy.

Pathophysiology of Lipodystrophy Mechanisms of Lipodystrophy The Effects of Protease Inhibitors

Different hypotheses have been put forward to explain the putative mechanism of HAART drugs in the development of lipodystrophy syndrome 116-120,122-124,126,134,141,147-152 . The first postulates that PIs primarily block cytochrome P450, which is involved in fat metabolism. The second postulates an interaction between PIs and human proteins. HIV protease has a sequence homology of 12 amino acids with two human proteins playing an important role in fat metabolism, namely, LDL-receptor-related protein (LRP) and cytoplasmic retinoic-acid-binding protein type-1 (CRABP-1). PIs inhibit both HIV protease and these two proteins. Inhibition of LRP leads to a reduction in the absorption of fatty acids by capillary endothelium and liver cells. This causes elevated serum triglycerides, visceral fat accumulation, buffalo humps, bull neck, insulin resistance, type II diabetes, breast hypertrophy, etc. Inhibition of CRABP-1 and cytochrome P450 3A isoform results in decreased cell differentiation and...

Dyslipidemia as a Risk Factor for Coronary Heart Disease

While smoking, hypertension, age, obesity, diet, and family history all contribute to CHD, dyslipidemia is one of the most prominent risk factors for this disease. Historically, CHD has often been considered a disease primarily associated with hyperlipidemia, i.e., high plasma cholesterol levels, particularly cholesterol associated with low-density lipoprotein (LDLc).4 Indeed, atherosclerotic plaques taken from heart transplant patients contained significantly higher percentages of cholesterol (19-26 +10 ) than nonatherosclerotic coronary tissue taken from the same donors (4 + 3 ).5

Adipose Tissue Dissolution and Hypertriglyceridaemia

Hypercholesterolaemia is often seen in tumour-bearing animals and in humans with cancer 10-12 . Interestingly, most cancer cells show an altered regulation in cholesterol biosynthesis, with a lack of feedback control on HMG-CoA reductase (3-hydroxy-3-methyl glutaryl CoA reductase), the key enzyme in the regulation of cholesterol biosynthesis. Cholesterol perturbations during cancer include changes in lipoprotein profiles, in particular an important decrease in the amount of cholesterol transported in the high-density lipoprotein (HDL) fraction. This has been observed in both experimental animals and human subjects 10-12 . HDL plays an important role in the transport of excess cholesterol from extrahepatic tissues to the liver for reutilisation or excretion into bile (reverse cholesterol transport). It is thus conceivable that the observed low levels of HDL-cholesterol are related, at least in part, to a decreased cholesterol efflux to HDL, as a consequence of increased utilisation and...

Lipoproteins Composition Structure Function and Lipid Transport

A proper balance between phospholipids and free cholesterol (FC) is required to maintain optimal cell membrane structure and fluidity.9 Many cells maintain their FC membrane requirements through endogenous biosynthesis. Other cells, including both the macrophages and underlying SMC involved in atherosclerotic lesion formation, acquire cholesterol by internalization of FC from lipoproteins. Because of their poor water-solubility, neutral lipids such as triglycerides (TGs), FC, and cholesteryl ester generally are not freely circulating in plasma, but instead are packaged together and assembled into larger lipoprotein particles that have amphipathic lipids and proteins as surface components. These submicroscopic spherical particles contain phospholipid (PL) and FC in the outer layer surrounding a core of neutral lipids, primarily cholesteryl ester and TG, held together by noncovalent forces. The cholesteryl ester found in the lipoprotein core is typically derivatized by saturated fatty...

Low Density Lipoprotein Cholesterol and Coronary Heart Disease Risk

The link between elevated plasma total cholesterol levels, high LDLc, and increased CHD risk has been known from epidemiological studies since the early 1980s. The Framingham Study followed over 5000 males and females, monitoring plasma lipid levels and the incidence of MI. In this cohort, subjects with elevated serum cholesterol ( 275 mgdL_ 1) had more adverse events whether they were healthy or already had CHD. The prevalence of plasma cholesterol levels above 240 mgdL_ 1 in subjects who experienced an MI was 35-52 in males and 66 in females.24 LDLc levels in this CHD subpopulation were well above 100mgdL_ 1 and were most prevalent at 160mgdL_ 1 Subjects who experienced an MI and had high plasma cholesterol levels were at increased risk for another MI or death from either CHD or other causes. Total cholesterol levels in FH patients exceed twice the normal range, and can reach higher than 500mgdL_ 1 in homozygous populations. LDL catabolism is dramatically lowered in these FH...

Markers of Inflammation and Oxidant Stress in Coronary Heart Disease

Currently, there are no validated biomarkers of either inflammation or oxidant stress that can be used predictably for drug intervention in CHD patients. C-reactive protein (CRP), whose biological function is undetermined, has been proposed as a potential marker of inflammation, particularly in patients with acute coronary syndromes (ACS).6 Whether CRP is produced in response to inflammation or contributes directly to an inflammatory response is still unknown. However, elevated plasma CRP levels may represent an independent risk factor for CHD in the general population, even in subjects with near-normal cholesterol levels.1'6 Subjects with the lowest quintile of plasma cholesterol had a twofold higher risk of CHD when their plasma CRP levels fell in the highest CRP quintile. Similarly, subjects having plasma cholesterol levels in the highest quintile doubled their CHD risk as their CRP levels increased from the lowest to the highest quintile. Subjects with near-normal cholesterol...

Low Density Lipoprotein Cholesterol Lowering Agents

Plasma cholesterol levels are determined by the balance between dietary intake, de novo biosynthesis, and reabsorption processes in the gut as well as by biliary clearance and excretion. While the majority of plasma cholesterol concentrations are derived from cellular biosynthesis in the body, primarily in the liver, about one-third is accounted for from absorption after dietary intake. Prior to the late 1980s, few alternatives existed to lower plasma cholesterol levels. While changes in lifestyle and diet were recommended, polymeric resins that sequestered bile acids in the gut, such as cholesteryamine and colestipol, were used to lower LDLc. While these agents were extremely safe due to their lack of systemic absorption, the high doses required for clinical efficacy limited patient compliance. Even at maximal doses of grams per day, these resins only achieved LDLc reductions of no more than 25 . Over the last 25 years, tremendous progress has been made in providing alternatives for...

Clinical efficacy of cholesterol absorption inhibitors as lowdensity lipoprotein cholesterollowering agents

Since dietary intake accounts for up to a third of plasma cholesterol levels and a redundant system in the enterohepatic recirculation is used to reabsorb and conserve cholesterol-derived bile acids and steroidal intermediates, various inhibitors of cholesterol absorption have been explored to identify alternative lipid-lowering agents. Such agents should provide an advantage over a simple low-fat diet and have particular benefit for patients who either do not respond or are unable to tolerate statin therapy. Ezetimibe 10 represents the first cholesterol absorption inhibitor approved for LDLc lowering. In clinical studies, daily doses of 0.25-10 mg of ezetimibe as monotherapy were safe and well-tolerated, and did not alter the plasma concentrations of lipid-soluble vitamins. In this study, ezetimibe dose-dependently lowered plasma LDLc, and the 10 mg dose lowered LDLc by 17-18 in hypercholesterolemic patients after 12 weeks of dosing.52 There was no statistically significant change in...

Fibrates as highdensity lipoprotein cholesterolelevating agents

Similarly, in the Veterans Affairs HDL Intervention Trial (VA-HIT), 2531 males with CHD having low HDLc (p40 mgdL _ 1), near-normal LDLc (p 140 mgdL _ 1), and elevated TG (p 300 mgdL _ 1) were treated for an average of 5 years with gemfibrozil.58 In this study, LDLc was not significantly altered, TG was lowered 31 , HDLc was raised 6 , and the combined number of CHD events was lowered 24 (a 2-3 decrease in CHD for every 1 rise in HDLc). In comparison, prospective statin trials showed only about a 1 reduction in CHD risk for every 1 decrease in LDLc (Table 4).34 However, attributing the event reductions observed in the VA-HIT trial exclusively to HDL elevations is confounded by the concomitant reductions in triglycerides. In contrast, no significant reductions in coronary events were observed in patients treated with bezafibrate 16 in the Bezafibrate Infarction Program (BIP) trial.

Mevastatin and lovastatin

The statin class was first identified in the early 1970s by investigators at Sankyo who discovered that the natural product, compactin (mevastatin 1), isolated from microbial fermentations of Penicillium citrinum in a search for new antimicrobial agents, potently inhibited HMG-CoA reductase and lowered serum cholesterol levels in animals.61 Compactin (Figure 7) also effectively lowered serum total cholesterol and LDLc in heterozygous FH patients. However, development was stopped in 1980 for unknown reasons that may have been related to toxicity issues that were uncovered in longer term animal studies.51

Low Density Lipoprotein Cholesterol Lowering Agents Cholesterol Absorption Inhibitors

Ezetimibe 10 was discovered as part of a program directed at identifying novel ACAT inhibitors for lipid lowering. These azetidinone leads, although weak as ACAT inhibitors, were efficacious in lowering cholesterol in animals, suggesting that they might work by a different mechanism.71-73 This discovery represents a tour de force in lead optimization, driven primarily by increasing in vivo efficacy by minimizing metabolism, and is in sharp contrast to the more common target-directed discovery approaches employed today. The biochemical target for ezetimibe was unknown at the time that discovery efforts began and has only recently been elucidated.74 Ezetimibe 10 has a long half-life, is suitable for once-a-day oral dosing, is rapidly absorbed, and becomes conjugated as its glucoronide metabolite that is excreted in the bile. This mechanism efficiently delivers ezetimibe to its site of action in the intestine, and recycling in the enterohepatic recirculation further insures that a high...

Ileal bile acid transporter IBAT and apical sodiumcodependent bile acid transporter ASBT inhibitors

As an alternative to cholesterol absorption inhibitors, specific inhibitors of the IBAT, also known as the apical co-dependent bile acid transporter are being sought. The IBAT system facilitates the reuptake of bile acids from the intestine, thus conserving the sterol pool. Functionally, an IBAT inhibitor should produce the same physiological effects of LDLc lowering achieved by anionic resins, such as cholestyramine, which sequester bile acids in the gut, without the high grams per day doses that dramatically limit patient compliance with sequesterants. The first entrant in this field, 34 (S-8921 Figure 14), has demonstrated oral efficacy in lowering LDLc with no accompanying change in HDLc at doses as low as 1 mgkg- 1 day-1.78 Development of 34 has been discontinued as it showed no clinical benefit over existing products.

Oxidized Ldl Is A Marker Of

The association of oxidative modification of LDL and stable angina and ACS has been studied (3). Table 1 shows characteristics of controls and patients with angiographically confirmed CAD. CAD patients were older more often male and smokers and had more frequently hypertension, diabetes, and hypercholesterolemia. CAD patients had higher levels of total and LDL cholesterol and of triglycerides, lower levels of HDL cholesterol, and 2.6-fold higher levels of oxidized LDL. Receiver operating characteristic (ROC) curve analysis revealed that oxidized LDL had a higher sensitivity for CAD than

Lipid Transport and Clearance Metabolism

Heparan sulfate is involved in regulating the metabolism of lipoproteins and major neutral lipids such as cholesteryl esters, triglycerides, and fatty acids. In the metabolism of lipoproteins, the endothelial cell surface heparan sulfate PGs have been shown to bind very low density lipoproteins (VLDL) through electrostatic interaction between positively charged regions of lipoproteins and negatively charged carboxyl- and sulfo-groups of heparan sulfate chains. Lipoprotein lipase, binding to this cell surface heparan sulfate PGs also, digests VLDL in capillaries

CASE 3 Changing Insulin Regimen Case Description

Despite close follow-up, he continued to have elevated blood sugars, particularly overnight, checking RMG at 3 AM. He had no defined exercise program, but leads an active lifestyle as a farmer. His current laboratory profile includes a fasting glucose of 234 mg dL and a glycosylated hemoglobin of 10.5 . A lipid profile showed a total cholesterol of 240 mg dL, an HDL cholesterol of 51 mg dL, an LDL cholesterol of 148 mg dL, and triglycerides of 60 mg dL. His creatinine was 0.9 mg dL. His examination was essentially normal with no evidence of diabetic neuropathy or diabetic retinopathy. In January 2000, he was started on an insulin infusion pump.

Mri Of Atherosclerosis Multi Contrast MRI of Atherosclerosis

Plaque components may be broadly grouped as lipids, fibrous tissue or thrombus intraplaque-hemorrhage. Plaque lipids are largely comprised of unesterified cholesterol, cholesteryl esters, and some lipoproteins (44). This makes them produce a short T2 resulting in low signal intensity on T2-weighted images (Fig. 1). The short T2 of the lipid portion of atheromatous plaque is believed to be the result of (i) the micelle-like structure of lipoproteins (ii) exchanges between cholesteryl esters and water molecules (iii) the results of oxidation and exchanges between free and bound water molecules (44,47,48). In contrast to plaque lipids, stored fat or adipose fat, such as may be found perivascularly, is mostly composed of triglycerides (49). Because of this, adipose fat found perivasculary has a different appearance on MRI compared to lipids found in atherosclerotic plaque.

Metabolic Abnormalities

The most important carbohydrate abnormalities are insulin resistance, increased glucose synthesis, gluconeogenesis and Cori cycle activity, and decreased glucose tolerance and turnover. The main pathological changes of protein metabolism include increased protein turnover, muscle catabo-lism, and liver and tumour protein synthesis, while muscle protein synthesis is decreased. The main abnormalities found in lipid metabolism are enhanced lipid mobilisation, decreased lipogene-sis, decreased lipoprotein lipase activity, elevated triglycerides and decreased high-density lipopro-teins, increased venous glycerol, and decreased glycerol clearance from the plasma 5,7,8 .

MRI of Aortic Atherosclerosis

There has been an array of studies looking at atherosclerosis in the aorta. One such study looked at asymptomatic patients from the Framingham Heart Study. In that study, it was shown by MRI that the atherosclerotic plaque prevalence and burden increased significantly with age (74). Interestingly, they also found that in their study group there was greater burden of disease in the abdominal aorta than in the thoracic aorta (74). In a similar analysis, it was found that asymptomatic aortic atherosclerosis detected by MRI was strongly associated with the Framingham Heart Study coronary risk score and other long-term coronary risk factors (75). Taniguchi et al. recently used MRI to study the relationship between aortic atherosclerosis and risk factors for coronary artery disease (CAD) (76). They found that thoracic atherosclerosis was closely linked to traditional risk factors for CAD such as high cholesterol, age, and smoking (76). In another study, Summers et al. used MRI to...

Mechanism of Action at the Cellular Level

The signaling pathways involving geranylgeranylated small GTPases that are affected by bisphosphonates and that lead to osteoclast apoptosis remain to be determined. Perhaps most proximal to the GTPases is the mammalian target of rapamycin (mTOR) ribosomal protein S6 kinase (S6K) signaling pathway.90 Signaling through this path is suppressed when geranylgeranylation is blocked in the osteoclast (Figure 2). Furthermore, specific inhibition of mTOR by rapamycin causes induction of osteoclast apoptosis over a similar time course to that of the N-BPs. Signaling through mTOR represents a relatively novel pathway downstream of receptor activator of NFkb (RANK), tumor necrosis factor alpha (TNF-a), and interleukin-1 (IL-1) signaling in the osteoclast.91'92 Downstream of phosphoinositol-3 kinase, signaling through the Akt kinase to mTOR was originally implicated in maintaining osteoclast survival, putatively through the regulation of protein translation, which itself was shown to be critical...

Liposomes And Lipid Nanoparticles

Biodegradable and nonbiodegradable polymeric nanoparticles are of great importance for their potential uses in controlled and sustained drug release 188 . Nevertheless, the cytotoxicity of the polymers after internalization into cells is a crucial and often less discussed aspect 189 . Also, large-scale production of polymeric nanoparticles can be challenging. Therefore, polymeric nanoparticle-based carrier systems have had limited success in terms of their commercialization. Therefore, considerable attention has been directed toward the development of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for their application as controlled delivery systems 190 . SLNs and NLCs consist of matrix prepared with biocompatible and biodegradable lipids or lipidic substances, which are solid, at both room and physiological temperatures 191 . SLNs based on pure triglycerides or waxes exhibit limited drug payloads due to the solubility of drug in the lipid that can lead to...

Management of Renal Dysfunction

Aside from the classic treatment of hypertension, an emerging approach to renal dysfunction is the treatment of the components that trigger endothelial dysfunction, e.g., NO bioavailability and oxidative stress. For example, oral treatment with L-arginine, the precursor of NO, reduces blood pressure and improves endothelial dysfunction in hypertensive patients.60 Statins and lipid-lowering drugs improve endothelial dysfunction in hypertensive animal models by enhancing NO levels.61 Antioxidants also can improve endothelial dysfunction in hypertensive animal models. For example, the SOD mimetic tempol decreases hypertension and oxidation stress and improves endothelium-dependent relaxation and kidney damage in hypertensive animal models such as AT-II-infused mice and Dahl salt-sensitive rats.62

Association With Other Risk Indicators

Another substudy from the IRAS study compared LDL-C with apoB as a correlate for a variety ofASCVD risk factors, including dyslipidemia, insulin resistance, hypertension, inflammation, thrombosis, and subclinical atherosclerosis (38). This interesting comparison examined differences between a group who had high LDL-C but normal apoB (i.e., high cholesterol mass distributed among a normal number of particles) and a group who had normal LDL-C but high apoB (i.e., normal cholesterol mass distributed among a larger number of particles). The latter hyper-apoB group had significantly higher TGs, fasting and 2-h insulin, and plasminogen activator inhibitor, and lower HDL-C, LDL particle size, and age than the group with isolated LDL-C elevation. This analysis raises the possibility that the normal LDL-C in the hyper-apoB group is not reassuring. Because apoB is a measure of particle number, this finding points to a discrepancy between the LDL-C and the number of atherogenic particles....

Cardiovascular Disease

The most common cause of death in the community, and of sudden death particularly, is cardiac disease, and within this group, those deaths recorded as resulting from ischemic heart disease or coronary atheroma are the most common. The exact definitions and criteria for the pathological diagnosis of significant ischemic heart disease (8) are not within the scope of this chapter. Although there is a clear increase in the incidence of this cause of death with age (9), it is important to remember that a small percentage of people in the younger age groups, most commonly those with hypercholesterolemia and hyperlipidemia, may also have significant coronary artery disease, and because the younger age groups are more likely to be arrested by the police, these few individuals may assume great significance.

Imaging Early Lesions

To address the hypothesis that PS binding sites on cells undergoing apoptosis in coronary atherosclerotic lesions of a human size large animal model are abundant enough to be detectable on in vivo single photon emission CT (SPECT) imaging swine underwent coronary injury followed by high cholesterol diet. Focal uptake of 99mTc labeled annexin V was visualized in the region of the heart corresponding to the distribution of the injured vessels confirmed by phosphor screen imaging (Fig. 1) (26). Pathology showed AHA class II and III lesions with the predominant cells being smooth muscle cells. Costaining for caspase-3 revealed the cells undergoing apoptosis to be smooth muscle cells. The apop-totic index calculated as caspase-3 positive cells over total cells correlated with lesional counts and there was a cut off value of 50 that separated scans that were positive and negative. This study showed that coronary lesions appearing as hotspots can be detected on in vivo gamma imaging in a...

Incorporating Lipoprotein Number Into Treatment Of Lipoprotein Disorders

We suggest that a practical way to approach hyperlipidemia is first to dichotomize patients into those with isolated LDL-C elevations and those with atherogenic dyslipide-mia (2). Those with isolated hypercholesterolemia would be managed according to the current ATP-III ATP-'04 recommendations. Those with atherogenic dyslipidemia would have an additional target of therapy based on some marker of LDL particle number (either apoB or directly measured LDL particle number). Although the superior evidence base and cost favor apoB for this purpose, assessing particle number by the NMR technique is a promising alternative (10). We agree with the Canadian guidelines that a measure of particle number should be an alternative to the primary (i.e., LDL-C) goal (4, 41), rather than an alternative to the secondary, non-HDL-C goal (10,28). Linking it to the ATP-III non-HDL-C goal might unnecessarily limit efforts to improve risk detection to those with TGs 200 mg dL. We have outlined our approach...

Coronary artery bypass grafts in the era of percutaneous coronary angioplasty

During those golden years for coronary surgeons and their patients, the results rapidly improved and the benefits became even clearer for all to see. Conduit choices were influenced by the enormous benefit that the left internal mammary artery conferred to the patient as clearly demonstrated by Loop. Different conduits, namely the right internal mammary, the gastroepiploic artery, the inferior epigastric and the latest version, the radial artery, have had their proponents. They were enthusiastically received and then underwent critical review. It is of interest that the latest fashion with the radial artery may, in the presence of statins, prove to be identical in 5-year graft survival to saphenous vein.

Impact ofLipid Lowering Agents on LpPLA2

Elevated levels of Lp-PLA2 may respond to a more aggressive approach to global risk reduction. This may include lifestyle modifications as well as drug therapy. A number of clinical studies were able to show that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a most pronounced effect on Lp-PLA2 plasma level, mainly owing to reduction in LDL-C, and that this effect remained strong and consistent in various populations. Indeed, in patients with type Ila and lib hyperlipidemia, treatment with atorvastatin resulted in the lowering ofLp-PLA2activity by 28-42 (45). In WOSCOPS, the use of pravastatin for 1 yr reduced Lp-PLA2 mass and activity by 17 (10). In patients with type 2 diabetes mellitus treated with fluvastatin, a 22.8 decrease in Lp-PLA2 (PAF-AH) activity has also been demonstrated, compared to an increase of 0.4 in the placebo group (p 0.001) (42). Furthermore, recently presented results from the Pravastatin Inflammation CRP Study, which included 481...

Diet and Physical activity

Terol intake with cardiovascular disease risk factors 37 . Results show concerning trends, with energy intake exceeding energy expenditure, suboptimal dietary calcium correlating with osteopenia, and dietary fat intake in levels that will not reduce cholesterol. These findings suggest that childhood cancer survivors would benefit from dietary interventions that match caloric intake with physical activity, optimize calcium and other nutrients needed for bone accretion, and reduce dietary fat.

Nanoparticlebased Drug Delivery

By Moulton et al. (24) in Apo E- - mice treated for four months (20 to 36 weeks) at a dosage of 30 mg kg every other day, 1.68 g kg total dose. Plaque angiogenesis and atheroma growth diminished despite persistent elevation of total cholesterol levels. We have shown the potential utility of a -targeted paramagnetic nano-particles to deliver antiangiogenic therapy in hyperlip-idemic rabbits (25). Ovft-targeted fumagillin nanoparticles significantly reduced aortic angiogenesis with a total dose of drug more than 50,000 times lower than the oral dose used in Apo E- - mice (24). We anticipate that the reduced dosage of therapeutic agent facilitated by targeted drug delivery approaches could substantially avoid the adverse effects previously reported for TNP-470 (26) or other potent agents. In clinical practice, we suggest that targeted fumagillin nanoparticles in combination with other standard care measures for hyperlipidemia (e.g., statins, dietary control, etc.) will allow prompt...

Vascular Dementia Diagnosis

Vascular dementia usually results from multiple CVAs or one significant CVA. It is generally considered the second most common cause of dementia after Alzheimer's disease, accounting for about 10 of all cases. Men are twice as likely as women to be diagnosed with this condition. Vascular dementia is characterized by a stepwise progression of cognitive deterioration with accompanying lateralizing signs. (See DSM-IV-TR diagnostic criteria, page 100) It is always associated with evidence of systemic hypertension and usually involves renal and cardiac abnormalities. Risk factors for the development of a vascular dementia include those generally associated with obstructive coronary artery disease, including obesity, hypercholesterolemia, smoking, hypertension, stress, and lack of exercise. The actual incidence of vascular dementia has decreased somewhat with better standards of care, improved diagnostic techniques, and lifestyle changes.

Abnormal Blood Cholesterol and Other Lipids

Cholesterol is necessary for a variety of bodily functions including the formation of plasma membranes and as a building block for hormones. Cholesterol is obtained through ingestion and synthesis in the body and is transported throughout the body by LDL and HDL. Elevation in plasma total cholesterol and LDL levels are clearly associated with increased risk of CVD, including CHD and stroke. High blood cholesterol levels are estimated to cause 4.4 million deaths annually that amount to over 18 of strokes and 56 of CHD.7 The current guidelines for plasma cholesterol and other lipids indicate that patients with total cholesterol of 240 mg dL _ 1 are twice as likely to experience heart disease as a person whose total cholesterol is less than 200mgdL_ 1. Similarly, patients with LDL cholesterol levels of 190mgdL_ 1 are considered as 'high risk' patients for CVD. In patients with diabetes or existing CHD, the LDL cholesterol level that places an individual at risk decreases to 130-159 mgdL_...

Other All TransRetinoic Acid Side Effects

ATRA side effects include dryness of lips and mucosae, isolated fever in the absence of other signs of ATRA syndrome (or infection), increases in transam-inases and triglycerides (which never required treatment discontinuation in our experience), and headache due to intracranial hypertension, which may be severe in children and associated with signs of pseudotumor cerebri (28). Lower ATRA doses (25 mg m2 d) can reduce this side effect in children (28).

Adrenoceptor Antagonists

A-Adrenoceptors are subdivided into two major classes, ai and a2, each of which has three subclasses. Antagonists of a adrenoceptors, e.g., quinazolines (prazosin, doxazosin, and terazosin), are antihypertensive (Figure 2). They are selective for a1-adrenoceptors, but not for any of the three subclasses (a1A, a1B, and a1D) Unlike older a-adrenoceptor antagonists phenoxybenzamine and phentolamine, quinazolines do not increase heart rate. Prazosin was widely used in the treatment of hypertension for a quarter of a century. The onset of action of prazosin is rapid the maximal antihypertensive effect is usually reached within 2 h of oral administration of the drug. An important advantage of prazosin and other quinazolines over thiazides or -adrenoceptor antagonists is their favorable effect on blood lipids they tend to decrease triglycerides and low-density lipoprotein, while increasing high-density lipoprotein cholesterol levels. Terazosin inhibits ex vivo platelet aggregation induced by...

Heavy Alcohol Consumption

For most adults, occasional moderate alcohol drinking (one to two drinks per day) is not harmful, and may have health benefits. Moderate alcohol drinking can increase the HDL-cholesterol level in the blood, decrease risk of blood clots, and reduce risk of heart attack.1 However, regular heavy drinking (more than three to four drinks per day) is a health hazard. (A drink is considered a 180-ml glass of wine, 360-ml glass of beer, or 30-45 ml of spirits.) Heavy drinking increases risk of high blood pressure, stroke, liver disease, im

Apolipoprotein E Genotypes

The apoproteins are the protein components of lipoproteins. There are five major apoproteins, labeled A-C, apo E, and apo (a), with subclasses that exist for many of these. Apoproteins function to activate enzymes in lipoprotein metabolism, maintain the structural integrity of the lipoprotein complex, and facilitate the uptake of lipoproteins into cells through surface receptors. Apo E is a 34-kDa glycoprotein found in all major lipoproteins except LDL. Apo E plays an important role in the transportation and metabolism of triglycerides, chylomicrons, and very low density lipoprotein (VLDL) remnants. There are three major isoforms of Apo E, designated as E2, E3, and E4, and are encoded by the apo E gene, located on chromosome 19, to produce the s2, s3, and s4 alleles. The s2 contains a cysteine in amino residues 112 and 158, the s3 contains a cysteine and argi-nine in these positions, and the s4 contains an arginine in both locations. The presence of the s4 genotype is associated with...

Sigwart U Puel J Mirkovitch V Joffre F Kappenberger L Reference

The greatest challenge for the interventionalist, is not the lesions that we treat, it is those that we leave. We rely on antiplatelet drugs, statins and angiotensin-converting enzyme (ACE) inhibitors to pacify these lesions. As our therapies improve, will there is any need for the inter-ventionalist in the future I think we are safe from extinction for the next 20 years, but after that all bets are off.

Statin Development and Classification

In search of a substance that lowers plasma cholesterol levels, Endo et al. tested more than 6000 fungi species, which finally, in 1973, led to the discovery of ML-236B 75 . ML-236B was subsequently termed mevastatin however, due to its severe side-effects, it never reached the market. Nevertheless, mevastatin is still frequently used in in vitro studies. Lovastatin (mevinolin) was the first statin to be approved by the Food and Drug Administration (FDA) in 1987. Currently, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin are available (Fig. 3). The new substance, rosuvastatin, was approved by the FDA in August 2003. Pitavastatin, as a very recent addition to the group, is currently available in Japan only. Statins are well tolerated and generally considered safe. Cerivastatin, however, was withdrawn from the market in August 2001, because it had the highest incidence of the overall rare side-effect rhabdomyolysis, and it is assumed to be involved in a total of 52...

Statin Mediated Effects on Inflammatory Markers

Several clinical trials have shown that statins reduce plasma levels of the acute-phase reactant C-reactive protein (CRP). In a population of 5742 patients enrolled in a randomised, double-blind, placebo-controlled trial of lovastatin in the primary prevention of acute coronary events, Ridker et al. found that lovastatin reduced the median level of CRP by 14.8 (95 confidence interval 12.5-17.4 , p 0.001) as compared to the placebo group during the first year of treatment 82 . This effect was unrelated to any change in lipid levels. This finding was still significant in a group of 1702 men and women with no prior history of cardiovascular disease 83 . After 24 weeks of doubleblind, placebo-controlled treatment, pravastatin reduced median CRP levels by 16.9 in this cohort (p 0.001 vs placebo). In a similar study, atorvas-tatin and pravastatin were recently found to reduce CRP levels significantly among 3745 patients with acute coronary syndromes within 30 days of initiation 84 ....

Effects on Reendothelialisation

Statins have been shown to decrease neointimal thickening in models of carotid injury 92,93 and also to reduce clinical events and angiographic restenosis after coronary stent implantation 94 . These effects were attributed to inhibition of smooth muscle cell proliferation 95 . However, recent research has provided insights into the profound effects of statins on endothelial cell function. Simvastatin and pravastatin have been demonstrated to activate phosphorylation of the protein kinase Akt in human umbilical vein endothelial cells 96 . Akt is involved in endothelial cell survival and blood vessel development 97 . It also protects cardiomyocytes from apoptosis 98 and activates endothelial nitric oxide production 99,100 . Daily intraperitoneal simvastatin injection led to enhanced Akt signalling in the ischaemic rabbit limb after femoral artery resection. This led to a highly significant promotion of capillary formation after 40 days of treatment (simvastatin 253 23 capillaries mm2...

Statin Mediated Effects on Endothelial Function

The vascular endothelium is an important source of mediators, which maintain an antithrombotic surface, regulate vascular tone, modulate inflammatory responses, and inhibit proliferation of vascular smooth muscle cells 105 . Nitric oxide (NO) is the most important such mediator. It is constitu-tively produced by endothelial nitric oxide synthase (eNOS). Statins have recently been found to improve the availability of NO, which leads to an improved endothelial function 106 . Some effects appear to be attributable to the inhibition of cholesterol biosynthesis. Indeed, substrates downstream from mevalonate in the synthesis cascade supply a number of metabolic pathways 106,107 . Geranylgeranyl-pyrophosphate is one such substrate, which serves as a lipid attachment to Rho, the latter being a GTP-binding protein. This protein coordinates a number of different cellular responses by interacting with downstream targets 109 , monocyte adhesion and transmigration through the endothelium 110, 111...

Blood Lipids and Heart Disease

Inulins and fructooligosaccharides help maintain the health of the cardiovascular system and may reduce the risk of heart disease. A key factor in this is the maintenance or improvement of blood lipid composition, through decreases in triglycerides (triacylglycerols), and the lowering of cholesterol and homocysteine levels (Hidaka et al., 2001 Luo et al., 1996 Tungland, 2003). Convincing lipid-lowering effects have been demonstrated in animals (e.g., Delzenne et al., 1993 Fiordaliso et al., 1995 Kok et al., 1998 Trautwein et al., 1998). Rats on inulin-rich diets, for example, had lower blood cholesterol and total lipid levels than control animals, while reductions in serum triglycerides were reported for rats on diets containing 5 to 20 fructooligosaccharides (Roberfroid, 1993). However, the situation is less clear-cut for humans, where higher inulin doses (over 30 gday-1) can produce adverse gastrointestinal symptoms (Williams, 1999). Some human studies have found no effects, while a...

Tracers for the study of triglyceriderich lipoprotein kinetics Chylomicrons

Triglyceride uptake from the circulation can under some circumstances occur independent of enzymes such as LPL and hepatic lipase. Saturation of transport appears to occur at plasma triglyceride concentrations of 400mg dL-1 (Brunzell et al. 1973, 1979) or lower (Nikkila & Kekki 1973). It is important to note that chylomicron-sized lipid particles can be removed via nonenzymatic pathways, particularly the reticuloendothelial system (Seidner et al. 1989). When large amounts of a lipid emulsion were administered to rats by bolus injection, there was evidence of non-enzymatic lipid clearance (Lutz et al. 1989). Karpe et al. (1997) concluded that, during mild chylomicronaemia after a high fat meal in normal subjects, the removal of triglycerides by non-lipolytic tissues was negligible. Quantitatively significant reticuloendothelial uptake may occur only at plasma triglyceride concentrations above those at which maximal rates of LPL-mediated triglyceride hydrolysis are observed, i.e....

Diagnosis and Management of MICS and Wasting Syndrome in CKD

Although epidemiological evidence strongly links inflammation to poor outcome in individuals with renal insufficiency, it must be recognised that as yet there are no randomised clinical trials to indicate improvement of cachexia and its outcome by inflammation-reducing approaches. However, some treatment modalities may target inflammation directly, or they may focus on oxidative and carbonyl stress or endothelial dysfunction. The following approaches may be considered (1) Statins (HMG-CoA reductase inhibitors) have been shown to decrease CRP levels independently of their lipid-lowering effects and may be associated with reduced mortality in CKD patients 180, 181 . (2) Angiotensin-converting enzyme inhibitors may have anti-inflammatory properties in both the general population and in CKD patients 182 , and are associated with delayed progression of chronic renal failure and improved outcome in these individuals 18 . (3) Vitamin E may have anti-inflammatory effects, and its...

A receptormediated pathway for cholesterol homoeostasis

Animal models of hypercholesterolaemia, as described in the preceding papers, as well as humans with familial hypercholesterolemia indicated an enormous potential for the role of cholesterol metabolism in atherosclerosis. Brown and Goldstein embarked on their studies of cholesterol homoeostasis in 1972, in an attempt to understand the human genetic disease, familial hypercholesterolaemia (FH), a disease characterized by marked hypercholesterolaemia with premature myocardial infarction. FH heterozygotes, carrying a single copy of a mutant low-density lipoprotein (LDL) receptor gene, are common accounting for about 1 in 500 persons. LDL levels are approximately doubled in these individuals and myocardial infarctions begin to occur in the 30 s and 40 s. The homozygous FH frequency is about 1 in a million persons and is characterized by a 6-10-fold elevation in LDL and myocardial infarctions beginning in childhood. The existence of the homozygous state facilitated the discoveries of Brown...

Chiral Drugs And Intermediates

BASF is producing vitamin B2 through fermentation. Diversia, a San Diego-based company has nitrilases useful for enantioselective one-carbon homologation of aldehydes, preparation of (R)-mandelic acid derivatives at enantiomeric excess (ee) of 99 , preparation of (S)-phenyl lactic acid at 99 ee, and enantioselective preparation of ethyl (R)-3-hydroxy-4-cyanobu-tyrate an intermediate in the synthesis of the cholesterol-lowering drug Lipitor.

Hyaluronan in Atherosclerosis

Experimental animal models of atherosclerosis induced by lipid feeding frequently have elevated levels of hyaluronan associated with developing vascular disease (20,46). Furthermore, atherosclerotic lesions present in apo E-deficient or LDL receptor negative mice and or rabbits are enriched in hyaluronan and macrophages. In addition, skin fibroblasts taken from patients with familial hypercholesterolemia that lack the LDL receptor exhibit elevated levels of hyaluronan synthesis in vitro (Goueffic, Sakr, Potter-Perigo and Wight, unpublished observations). Such results indicate that lipids may modify hyaluronan production in such a way as to promote a pro-inflammatory pro-atherosclerotic condition. Thus, it is clear that early lesions that contain excess lipid are usually enriched in hyaluronan. Such a concentration of molecules that soften and swell the tissue could very well weaken the plaque and predispose the plaque to rupture.

Age Related Macular Degeneration

Although clinical trials for several different approaches to treat dry AMD could in theory be justified based on clinical observations and preclinical research (e.g., statins, apoptosis inhibitors, and anti-inflammatory drugs), there are only a few methods currently being investigated in clinical trials. One is the use of the carotenoid pigment, lutein (Figure 4) as an oral supplement. In theory the anti-oxidant and preferential retinal accumulation properties of lutein would be expected to have a salutary effect on dry AMD progression, but the unexpected negative effect of b-carotene consumption on lung cancer development in smokers counsels caution.

Unmet Medical Needs

Androgen replacement therapy has been reported to cause water retention, polycythemia, hepatotoxicity, sleep apnea, prostate enlargement, and to reduce HDL cholesterol.3 Hepatic toxicity is associated with derivatives of testosterone rather than pure testosterone. Polycythemia is observed more commonly in males receiving injectable testosterone. Thus, hematocrit should be measured periodically to minimize the risk of polycythemia. HDL cholesterol lowering is more profound with oral methyltestosterone than transdermal or injectable testosterone, but this effect is dose dependent, with higher doses causing more profound lowering of HDL cholesterol. Although testosterone is associated with prostate enlargement and prostate cancer, testosterone replacement therapy is rarely associated with an increase in urinary tract voiding symptoms, leading to cessation of therapy. In addition, prostate cancer surveillance can be done by measurement of PSA during the first 6-month interval after...

Roles of Transporters in Pharmacokinetics

This huge network of hepatobiliary transporters can give rise to variations in drug disposition between individuals by modulating the uptake or the exit of drugs and their metabolites from hepatocytes. A change in hepatic uptake may have clinical consequences. It may modulate the pharmacological activity of drugs that act via the intrahepatocellular transduction pathways, it may cause hepatotoxicity, or give rise to drug-drug interactions. The concentration of the cholesterol-lowering HMGCoA inhibitors in hepatocytes must be adequate for their pharmacological activity, and most of the statins (e.g., pravastatin, simvastatin, lovastatin, cerivastatin, and pitavastatin) enter hepatocytes via OATP1B1, and to a lesser degree via OAT1B3.131 Recently identified genetic polymorphisms like the SLCO1B3 haplotype *17 are associated with reduced statin clearance by the liver and lower concentrations in hepatocytes they thus have less effect on cholesterol synthesis.132 Large-scale clinical...

Ira J Goldberg MD and Phillip Bukberg MD

Case 3 Familial Hypercholesterolemia Case 4 and 5 Unusual Levels of HDL Cholesterol His primary care physician followed the patient for the next 3 yr with no change in his medications and no new symptoms. Two weeks prior to his visit, he was seen for a routine evaluation. He now weighs 210 lbs. His cholesterol was 240 mg dL, triglycerides 600 mg dL, HDL 25 mg dL, and LDL was not estimated. You order several additional tests including Lp(a), small dense LDL measurement, glucose and HA1c. Lp(a) was less than 30, LDL was pattern B (more small dense LDL), fasting glucose was 160, and HbA1c was 8.0 . In the course of treatment for his anginal syndrome, this man was appropriately given P-blockers and a cholesterol-lowering medication, simvastatin. Although P-blockers have been reported in one study to be associated with increased development of diabetes (2), their positive effects to reduce cardiac death make their usage in this situation appropriate. It should also be noted that, as in...

Biochemical Mechanisms

Examples of futile cycles include the synthesis and degradation of proteins, the pumping and leakage of ions across membranes, and esteri-fication and lipolysis of fatty acids triglycerides. Since the activity of these futile cycles is difficult to assess in intact organisms, it has been difficult to determinate their importance in adaptive ther-mogenesis. A clear example of uncoupling as a means of increasing energy expenditure is that brought about by uncoupling protein-1 (UCP1), a mitochondrial inner-membrane protein that leaks protons across the mitochondrial inner membrane. The energy that is stored in the mitochon-drial proton electrochemical gradient is released 8 in form of heat and is not used to synthesise ATP. UCP-1 is expressed at very high levels in BAT, the primary function of which is to produce heat in response to cold exposure. Other homologues of UCP-1 (UCP-2, UCP-3, UCP-4, and UCP-5) have been found in other tissues, but they do not appear to play an...

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