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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Author: Scott Davis
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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

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...

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 (< 31 mgdL_ 1) and normal LDLc levels were treated with a combination of simvastatin and niacin. This combination produced an elevation of 26 in HDLc and a surprising 42 reduction in LDLc. These combined effects on lipids were accompanied by a remarkable 60-90 reduction in CHD events. Since this was a small trial, it would be useful to have these results confirmed in a larger...

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,...


The ability of statins to lower hsCRP was first described for pravastatin using data from the CARE trial (94,101). Subsequent confirmatory work has shown the effect of statins on hsCRP to be an important class effect. A meta-analysis of the effects of statins on nonlipid serum markers specifically CRP, fibrinogen, homocysteine, LDL-C oxidation, tissue plasminogen activator, plasminogen activator inhibitor, and platelet aggregation concluded that, of these, only CRP appears to be influenced by statin use (102). Indeed, studies of pravastatin, lovastatin, cerivastatin, simvastatin, and atorvastatin indicate that, on average, median hsCRP levels decline 15-25 as early as 6 wk following initiation of therapy (102) in persons with no history of CVD (48,103-106) and in patients with stable coronary disease (103,107) or ACS (90,108). Ezetimibe, a novel cholesterol absorption inhibitor that prevents absorption of dietary and biliary cholesterol without affecting that oftriglycerides and...

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.

Motivation for the use of intermediate endpoints or surrogates

Ideally, when studying the effects of an E I, the appropriate outcome measure is the true clinical end-point of interest (CE), which is usually survival or the incidence of a clinical event. However, the CE may require invasive tests, be expensive, occur rarely or be temporally distant from the E I. For example, in trials of cholesterol-lowering drugs, the fundamental end-point of interest may be death or development of coronary artery disease (CAD). Such a study may require the recruitment of thousands of patients followed up for many years. Clinicians, patients and funding bodies are keen to assess the effectiveness of promising new therapies quickly. This leads investigators to explore markers that may serve as intermediate end-points or surrogate end-points (IE Ss) of the CE and which are more frequently occurring and temporally closer to the E I. Therefore, for example, it is of interest to know how useful a reduction in post-treatment cholesterol will be in predicting reductions...

Defining intermediate endpoints or surrogates

The second point implicit in the Prentice criterion is that the IE S is chosen in a way that depends on the interventions under comparison. For example, cholesterol reduction may serve as an IE S for CAD in a trial of a cholesterol-lowering drug, but it is unlikely to be useful in a study of antihypertensive drugs. In addition, once validated, cholesterol may be a valid IE S for trials of other cholesterol-lowering agents, but not for an E I acting via a different pathway. Universal IE Ss which apply for all E Is are very rare. This point is directly related to the position of the IE S on the disease pathway. Cholesterol changes may serve as an IE S for CAD provided that the treatments under study do not differentially affect CAD via pathways that bypass the cholesterol-lowering effect - if they have a side effect of raising blood pressure, for example.

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...

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...

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...

The Design of Ezetimibe

In parallel, we studied the synergistic effect of ezetimibe, along with a statin for lowering cholesterol levels. Thus, ezetimibe (0.007 mgkg_ and lovastatin (5mgkg_ were administered orally to two different sets of chow-fed dogs for 14 days. Neither ezetimibe nor lovastatin showed significant activity however, the combination showed a dramatic reduction in serum cholesterol levels (Figure 6). Based on all these results, ezetimibe has progressed to the clinic as a monotherapy agent and also in combination with simvastatin. The combination drug, named Vytorin, was jointly developed by Schering-Plough and Merck. Based on all these observations, ezetimibe was advanced alone and also in combination with simvastatin and atorvastatin in the clinic, and the results are presented in Figure 7. In the clinic,10-13 ezetimibe (10 mg) when administered alone reduced serum cholesterol levels by 18.5 , on average, and in combination with simvastatin (10 mg), serum cholesterol levels were reduced by...

Regulation of endogenous glucose output during euglycaemic hyperinsulinaemia

Several metabolic conditions known to be associated with resistance of insulin induced suppression of endogenous glucose output should be considered when a clamp protocol is planned. For example, impaired glucose tolerance (Bavenholm etal. 2001), type 2 diabetes mellitus and obesity (Kolterman etal. 1981 DeFronzo etal. 1985 Butler etal. 1990 Staehr etal. 2001 Krssak etal. 2004), steroid therapy (Rizza etal. 1982), increased availability of free fatty acids and or triglycerides (Bajaj et al. 2002 Boden et al. 2002) and fat accumulation in the liver (Seppala-Lindroos etal. 2002 Krssak etal. 2004) are associated with defective insulin induced suppression of endogenous glucose output. In terms of a dose-response curve of insulin action on endogenous glucose output, the curve is shifted to the right under these metabolic conditions, indicative of hepatic insulin resistance (Kolterman etal. 1981). In line with these studies, the half maximal effective plasma insulin concentration to...

Fields Of Expertise Within Toxicology

Cirrhosis of the liver is one of the most well-known adverse effects of chronic alcohol abuse. The cholesterol-lowering, life-prolonging statin drugs must be monitored routinely for hepatotoxicity and rhabdomyolosis. A Google search on the terms statins, hepatotoxicity, and review produced over 22,000 hits indicating this is a very active field of interest.

Figure 15 Structure of the cofactor uridine5diphosphoaDglucuronic acid 39 UDPGA generic reactions of O and

An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.

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

Regression of coronary artery disease as a result of intensive lipidlowering therapy in men with high levels of

BACKGROUND AND METHODS The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2.5-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments lovastatin (20 mg twice a day) and colestipol (10 g three times a day) niacin (1 g four times a day) and colestipol (10 g three times a day) or conventional therapy with placebo (or colestipol if the low-density lipoprotein LDL cholesterol level was elevated). RESULTS The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7...

Nonsteroidal Antiestrogens

It is relevant to point out that the antiestrogen MER25 is a structural derivative of the cholesterol-lowering drug triparanol (MER29) (Figure 1). In the late 1950s there was initial enthusiasm about the potential benefits of triparanol as a hypocholesterolemic drug.14 However, the finding that triparanol caused an accumulation of desmosterol (an intermediate in cholesterol biosynthesis)15-18 and the linking of this biochemical effect to cataract formation,19-21 caused withdrawal of the drug in 1962 (Figure 2). Nevertheless, triparanol was first evaluated as a potential therapy for breast cancer22 but again the results were disappointing. Figure 2 The mechanism of action of triparanol is to inhibit cholesterol biosynthesis but also to increase demosterol levels which is implicated in cataract formation. In contrast, tamoxifen has an alternate mechanism of action to lower cholesterol levels.

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...

Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

Cholesterol plasma levels are part of the syndrome. Total cholesterol levels are not constantly increased, but occasionally can be remarkably high 25 (Table 3). Muscle mass, evaluated by DEXA, is preserved on even increased compared with age-, sex- and BMI-matched subjects. The increase in resting energy expenditure is related to the higher fat-free mass body mass ratio. Two subtypes of CGLD have been identified and are distinguished according to the mode of inheritance 26-29 . Type 1 CGLD is related to an autosomal recessive genetic defect in AGPAT2 isoform. This enzyme, involved in the biosynthesis of triglycerides and phospholipids, is expressed at high levels in adipose tissue. Thus, a defect in AGAPT function may reduce triglyceride synthesis in fat cells. Type 2 CGLD is related to an autosomal recessive involvement of seipin, a protein of unknown function 30 . Mutation of the seipin gene has been reported to cluster in a large consanguineous pedi-

Congenital Partial Lipodystrophy Type 1 Dunningam Syndrome

Atrophy of the subcutaneous fat layer usually manifests at puberty, involving the arms, legs, and buttocks. The subcutaneous adipose tissue of the face, neck, and intra-abdominal area may be preserved, giving patients a silhouette of visceral obesity. An increase in intramuscular fat has been reported. Insulin resistance, reduced glucose tolerance, overt diabetes, hypertriglyceridaemia, and low levels of HDL cholesterol are associated with Dunningam syndrome and lead to early onset of atherosclerotic vascular diseases. Acute pancreatitis and liver steatosis may complicate the clinical picture. The identification of missense mutations on chromosome 1q 21-22, involving genes encoding lamins A and C, in affected members of a family suggests the molecular basis of the disease 33 . Lamins provide structural integrity to the nuclear membrane, such that mutations in the HDL cholesterol Triglycerides

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.

Background and Introduction

ERT gained widespread popularity in the US in the 1960s and early 1970s26-28 and, by 1974, approximately 28 million prescriptions were filled for noncontraceptive use of estrogens. Previous studies have shown that ERT slows the rate of postmenopausal bone loss22,29 and reduces the incidence of osteoporotic fractures,22 and until recently, it was generally believed that ERT might be beneficial for reducing the risk of heart disease.30,31 The idea that ERT might have cardioprotective effects was based on observational studies32-37 which suggested that women who take estrogen have a lower risk of CHD compared to women who do not take estrogen. Previous studies38-40 have shown that estrogen therapy reduces plasma levels of the 'bad cholesterol' low-density lipoproteins (LDL) and increases the levels of the 'good cholesterol' high-density lipoproteins (HDL), changes that are associated with a reduced risk of cardiovascular disease. Estrogen also prevents oxidation of LDL cholesterol, which...

Atherosclerosis no longer a bland lipidstorage disease

Once resident in the arterial intima, mononuclear phagocytes change their character and acquire the characteristics of foam cells. After penetrating into the intima, the blood monocyte expresses scavenger receptors, allowing it to take up modified lipoproteins that accumulate in the subendothelial space. The scavenger receptors evade the usual homeostatic suppression by excessive cholesterol characteristic ofthe classic low-density lipoprotein (LDL) receptor. This untrammeled ability to take up lipoproteins leads to the formation of lipid-laden macrophages known as foam cells, the hallmark of the early atherosclerotic lesion, also known as the fatty streak. Macrophages within the artery wall can also divide and elaborate reactive oxygen species and proinflammatory cytokines that can sustain and amplify intimal inflammation (9,10). Several proinflammatory mediators likely participate in signaling proliferation and activation of the macrophages present in the plaque. One prominent...

Could Levels ofCirculating Biomarkers ofInflammation Help Guide Therapy

A retrospective analysis of CRP levels in a large primary prevention trial, Air Force Coronary Atherosclerosis Project Texas Coronary Atherosclerosis Project, suggested that apparently healthy individuals with below median LDL levels but above median hsCRP levels derived benefit from statin therapy (39). Curiously, individuals with both below median LDL and below median hsCRP levels did not benefit from treatment, indicating that promiscuous use of statins in primary prevention likely would not prove cost-effective and would expose one-fourth of the apparently healthy population to potential risks and expensive drug treatment without benefit.

Inflammatory Biomarkers and Clinical Utility

A more optimistic position would argue that residual risk indicated by inflammatory biomarkers in an optimally managed patient could provide impetus for intensification of lifestyle measures to ameliorate the individual's inflammatory profile. Weight loss, dietary interventions, smoking cessation, and regular physical activity may all mitigate inflammation beyond pharmacotherapy. Statins have received the greatest attention as pharmacological modifiers of inflammatory biomarkers. However, increasing evidence supports the possibility that other classes of medications may likewise modulate inflammation. Although aspirin has not consistently reduced levels of CRP, emerging evidence suggests that fibric acid derivatives, thiazolidinediones, and metformin can reduce such levels. The fibric acid derivatives can limit inflammation by activating peroxisome proliferator activated receptor-a (PPAR-a). The thiazolidinediones (e.g., the glitazone class of insulin...

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 (< 0.95 g mL), very low-density lipoproteins (VLDL, 0.95-1.006 g mL), intermediate-density...

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 .

HsCRP Metabolic Syndrome and Type 2 Diabetes Mellitus

Clinical practice, such as elevated triglycerides, low HDL-C, obesity, high fasting glucose, and high blood pressure (BP). In the Women's Health Study, e.g., after adjustment for multiple potential confounders, the RRs of incident hypertension for increasing hsCRP quintiles were 1.00 (referent), 1.07 (95 CI 0.95-1.20), 1.17 (95 CI 1.04-1.31), 1.30 (95 CI 1.17-1.45), and 1.52 (95 CI 1.36-1.69), respectively (p for trend of < 0.001) (73). hsCRP levels are also correlated with other components of the syndrome not easily assessed during routine office visits, such as fasting insulin, microalbuminuria, and impaired fibrinolysis. Indeed, among Women's Health Study participants without diabetes, hsCRP and BMI were the only independent correlates of fasting insulin level modeled as a continuous dependent variable. After adjustment for BMI and other risk factors for diabetes, the RR for elevated fasting insulin ( 51.6 pmol L) increased with the tertile of hsCRP (for hsCRP < 1.4, 1.4-4.4,...

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...

Exercise and Epilepsy

The benefits of aerobic and weight-bearing exercises are well established. Exercise improves the course of many chronic illnesses and, in some cases, prevents them. The signs and symptoms of hyperlipidemia (elevated triglycerides and cholesterol), high blood pressure, obesity, coronary artery disease, osteoporosis, and diabetes are all improved by regular exercise however, the benefits of exercise for epilepsy are less well established, and as a result, not routinely prescribed by most clinicians at comprehensive epilepsy centers.

Longevity Studies With Mated Males and Females

Thep values were calculated using a mixed model analysis of covariance (covariates live weight LW and total protein content Pro for triglycerides TG live weight and total triglyceride content for protein and total protein and triglycerides for live weight). The mean numbers are shown with the standard deviations in parentheses. Con, control diet PA, palmitic acid diet BF, beef diet NS, not significant compared with control. Thep values were calculated using a mixed model analysis of covariance (covariates live weight LW and total protein content Pro for triglycerides TG live weight and total triglyceride content for protein and total protein and triglycerides for live weight). The mean numbers are shown with the standard deviations in parentheses. Con, control diet PA, palmitic acid diet BF, beef diet NS, not significant compared with control.

Practical considerations

The study of lipoprotein triglyceride fatty acid kinetics has been challenging because of the unavailability, until recently, of primary pool tracers. When chylomicron or VLDL triglycerides are labeled with a precursor (e.g. oral ingestion of a labeled triglyceride or fatty acid in the case of chylomicrons oral or intravenous administration of labeled glycerol in the case of VLDL), the rate of tracer appearance into the primary pool is not known. Measurement of kinetics under non-steady state conditions is problematic because there is often ongoing tracer appearance at an unknown rate and therefore simultaneous tracer disappearance at an unknown rate. This problem can be circumvented with the direct administration of labeled chylomicrons (or a surrogate thereof, such as a lipid emulsion) or labeled VLDL. The relatively recent availability of such tracers should improve the reliability of measurements made under steady state conditions and should also make it possible to attempt...

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...

Protein Metabolism in Diabetes Mellitus

Proteins are one of the major body fuels however, despite the large size of the protein pool, only about 15-20 of daily calorie consumption is accounted for by protein oxidation, while fat accounts for about 30 and carbohydrates for 50 or more. There is no 'storage' form for amino acids - in contrast to glycogen and triglycerides, which are the storage forms for glucose and free fatty acids, respectively. Body proteins are not a fuel reservoir in themselves instead, protein molecules have specific roles in maintaining organ structure and function. Both the synthesis and the degradation of proteins are metabolically expensive relative to other fuels, i.e. glycogen and triglycerides. Glycogen synthesis requires 3 ATP per glucose added, and one of these ATP is recovered during glycogenolysis. Triglycerides synthesis requires only 2 ATP per fatty acid molecule added. Formation of just one peptide bound requires at least four high-energy phosphates that are not

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

Effects on Metabolism and Energy Expenditure

Both the synthesis and the degradation of triglycerides and cholesterol are increased in TS, but the net effect is one of lipid degradation, as reflected by an increase in the plasma concentrations of free fatty acids and glycerol, and the decrease of serum cholesterol level. Serum triglyceride levels are usually slightly decreased 18 .

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).

Kip KE Faxon DP Detre KM Yeh W Kelsey SF Currier JW Reference

This study was performed prior to the availability of a number of systemic therapies for diabetic patients that would favorably affect their long-term prognosis, including better agents for glycaemic control, lipid-lowering therapy with statins, angiotensin-converting enzyme inhibitors, and beta-blockers. This study was also performed before the availability of coronary stents, and now drug-eluting stents, but these therapies are not useful in preventing late mortality in patients with coronary artery disease.

Nutraceutical Supplements

Fructooligosaccharides have been used as food supplements in Japan since 1983. A wide range of inulin-containing functional foods are marketed as beneficial for gastrointestinal conditions and for the promotion of mineral absorption (Hidaka et al., 2001). Over 700 products in Europe included inulin as a nutraceutical ingredient by 2000, including yogurts. One of these yogurts became the first functional food to have its health-promoting claims challenged in court. The yogurt, containing Lactobacillus acidophilus and inulin, was claimed to have cholesterol-lowering properties. The claim was upheld and the company (Mona, The Netherlands) won the case (Heasman and Mellentin, 2001).

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

Nutritional Support

Catecholamines and cytokines, which are elevated in heart failure, are stimuli for free-radical production. Therefore, antioxidants and free radical scavengers, such as vitamins C and E, are therapeutic options in cardiac cachexia. This was proven by a study showing that muscle wasting in mice was prevented by an antioxidant 92 . Additionally, it was shown that antioxidants suppress the production of free radicals in leucocytes 93 . The presence of elevated levels of markers of oxidative stress in heart-failure patients correlates with functional class, reduced exercise tolerance, lower antioxidant levels, and worse prognosis, including cachexia 94, 95 . These patients also tend to have micronutrient deficiency through, e.g. urinary losses or therapy with diuretics. Deficiencies of specific micronutrients, such as selenium, copper, calcium, zinc, or thiamine, can also cause heart failure 96 . Thus, it is important to keep CHF patients on a diet with sufficient calories and with...

Clinical Features

Consideration of the mode of inheritance in progeria is important for genetic counseling and may help to understand the nature of the underlying mutation. Recessive diseases often appear to be caused by enzymatic deficiencies that lead to metabolic abnormalities. Dominant diseases often involve structural proteins. However, they may be due to partial deficiencies of rate-limiting enzymes (i.e., porphyria) or cell surface receptors (i.e., familial hypercholesterolemia) where half the normal level of the gene product can lead to a disease.

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...

Management of the Metabolic Syndrome

Finally, because of the heightened risk of vascular disease, MetS patients should receive other broad-spectrum preventive treatments such as aspirin. The targets for lipids and blood pressure should follow guidelines and recommendations for higher-risk patients. The treatment of the atherogenic dyslipidemia in MetS is aimed at correcting the fundamental disturbances - namely reducing plasma triglycerides and raising plasma HDL cholesterol. Among currently available agents, the fibrates, which are PPAR-g agonists, are best at normalizing MetS dyslipidemia. In contrast, statins target LDL cholesterol, but their role in vascular disease prevention is supported by a much wider evidence base. Many clinicians will first choose a statin as dyslipidemia therapy for MetS patients, especially when triglycerides are only mildly elevated. Other treatment alternatives include the judicious use of niacin preparations and also combinations of a fibrate, statin, and or cholesterol absorption...

Clinical Role Of Crp Testing

Accumulating evidence suggests that statins may have powerful antiinflammatory effects (39,40). Indeed the risk reduction observed with these agents in large-scale clinical trials have been greater than that explained on the basis of changes in lipid parameters alone. In this regard, several studies have recently demonstrated that statins reduce CRP concentrations, and that this effect is independent of lipid lowering (41-44). Data from the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention study, indicates that statins may be most effective among patients with evidence of persistent inflammation (45). The CARE trial randomized patients with a prior history of MI to receive either pravastatin or placebo (46). Patients with evidence of persistent inflammation (as evidenced by an increase of both CRP and serum amyloid A) were at increased risk of recurrent cardiovascular events (45). The study group with the highest risk of recurrent events was that of patients with...

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 < 100mgdL_ 1 (< 70mgdL_ 1 in individuals with known coronary artery disease), HDL cholesterol of > 40mgdL_ 1 (> 50 mgdL_ 1 in women), and triglycerides < 150 mgdL_ 1. Low-density lipoprotein (LDL) cholesterolb Diabetes + coronary heart disease High density lipoprotein (HDL) cholesterolc Triglycerides aHbA1C is the primary target for glycemic control. Glycemic goals should be individualized, with certain populations...

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.

Changing Patterns of Cachexia in the HAART

Prior to 1996, only a small percentage (3 ) of patients developed hypercholesterolaemia, hyper-triglyceridaemia, and diabetes. The main fat disturbances in cachexia are a decrease in cholesterol levels, an increase of triglycerides, and a global loss of fat together with lean tissue in any body region. These patterns can be clearly distinguished from lipodystrophy (Table 6). HDL cholesterol Triglycerides Hyperlipidaemia (cholesterol, triglycerides)

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...

Body fat distribution and insulin resistance Skeletal muscle intramyocellular lipids

Overabundance of plasma triglycerides and free fatty acids entering the circulation by lipol-ysis from adipose tissue or by ingestion from food is frequently associated with pathophys-iology of insulin resistance and diabetes mellitus (Defronzo 2004). Results of radioactive Another metabolically active source of triglycerides that could influence cellular glucose uptake is the lipids stored in the cytosol of non-adipose tissue. Such lipid vesicles can be found in the skeletal muscle, myocardum, liver and pancreatic P-cells. These fat depots are not released into the circulation, but may influence glucose utilisation directly. Early evidence from histological and biochemical skeletal muscle biopsy analysis have shown a correlation between skeletal muscle triglyceride aggregation and insulin resistance (Phillips et al. 1996 Pan et al. 1997 Ebeling et al. 1998). These techniques, however, could not sufficiently discriminate between intramyocellular (IMCL) and extramyocellular (EMCL)...

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...

Prognostic Role of BNP and NTproBNP Across Spectrum of ACS

A substudy ofthe Orbofiban in Patients with Unstable Coronary Syndromes-Thrombo-lysis in Myocardial Infarction 16 (OPUS-TIMI 16) trial was among the first to evaluate the prognostic capabilities of BNP in a large population of patients across the entire spectrum of ACS (45). In this study, BNP was measured in 2525 patients at a mean of 40 h after presenting with STEMI, NSTEMI, or unstable angina. BNP levels on admission correlated with age, male gender, white race, hypertension, CHF, peripheral vascular disease, hypercholesterolemia, and smoking status. In addition, elevated levels of BNP were associated with Killip class > 1, electrocardiogram (ECG) changes, elevated creatine kinase-MB, and chronic kidney disease. A plasma concentration of BNP > 80 pg mL was a powerful

High Density Lipoprotein Cholesterol Elevating Agents

Epidemiological studies clearly indicate that low HDLc (< 40mgdL_ 1) represents a significant independent risk factor for CHD. While statin therapy effectively lowered LDLc by up to 45 , statins generally produce only very modest increases in HDLc levels, usually less than 10 .34 Currently, only two alternatives are available for treating low HDLc fibrates and niacin-based (Figure 8) therapies. Fibrates increase HDLc by 10-15 , but have a more pronounced effect on TG lowering. Fibrates have been available since the early 1970s. The fibrate mechanism of action

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

Proposed Application Of Bnp In

At the present time, adequate data do not exist to define the proper role of BNP and NT-proBNP in stratifying patients to more aggressive interventional therapy, and the clinician must consider plasma levels of these peptides in the context of other biomarkers and clinical factors before assigning a patient to a proper level of care. More research is needed to identify appropriate pharmacological and interventional strategies for high-risk patients with ACS and elevated levels of BNP or NT-proBNP. In the meantime, we propose the algorithm in Fig. 7 for patients with ACS. Patients who present with ACS and have elevated cardiac troponin or who are in a high TIMI risk category have been shown to benefit from an early interventional approach. In patients with a low TIMI risk score who have a normal troponin result, aggressive intervention may be considered for those patients who have BNP levels > 80 pg mL (cut point based on studies using the Biosite and Bayer assays). Otherwise, a...

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 2 Latent Autoimmune Diabetes In Adults Case Description

Laboratory results referral included a glycosylated hemoglobin of 10.4 (normal range 4.0-7.0 ). Fasting glucose was 79 mg dL. His creatinine was 1.2 mg dL. Lipid profile yielded total cholesterol of 243 mg dL, triglycerides of 116 mg dL, HDL of 78 mg dL, and LDL of 142 mg dL. Spot test for microalbuminuria (ratio of albumin creatinine) was 72 g mg (normal range- < 30 g mg).

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.

Clinical Trial Issues

A 125 mg dose of hydroalcoholic gel of DHT applied twice daily to the skin can result in sustained concentrations of DHT.24 As expected, the ratio of DHT to testosterone increased to around 5 (normal ranges between 0.1 and 0.2) serum testosterone, estradiol, and SHBG concentrations did not rise and gonadotropins were unchanged. Treatment of testosterone-deficient hypogonadal males reportedly improved virilization and sexual function and decreased plasma low- and high-density lipoprotein (HDL) cholesterol levels moderately without causing enlargement of the prostate as determined by ultrasound study.24

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.

Nitrogen Containing Bisphosphonate Inhibition of the Cholesterol Biosynthetic Pathway

Over 15 years ago, it was shown that certain BP derivatives (isoprenoid (phosphinylmethyl) phosphonates) weakly inhibit the cholesterol biosynthetic enzyme squalene synthase.51 The search for more potent inhibitors that might block cholesterol production revealed that the N-BPs incadronate (YM175) and ibandronate potently inhibit squalene synthase.52 Subsequent studies examined the structure-activity relationship (SAR) for inhibition of squalene synthase.53-55 In vivo testing showed that certain compounds suppressed serum cholesterol in rodents.53 Other cholesterol-lowering bisphosphonates were shown to trigger degradation of hydroxymethylglutaryl coenzyme A (HMG-CoA).56-58 In the same context, utility of squalene synthase inhibition by bisphosphonate was also used for the development of an assay to measure zoledronate levels in animals and clinical serum samples.59 Although cholesterol itself is important for osteoclast signaling and survival, the osteoclast relies on low-density...

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