Natural Cholesterol Lowering

Lower Cholesterol Guide

Scott Davis is an Australian writer, medical researcher, alternative health expert and former cholesterol sufferer, whose cholesterol was once over 300. He did everything that his doctor told him to, but his cholesterol didnt go down. When his doctor told him that he would need surgery if it didnt come down he went on a mission to write the Beat Cholesterol ebook. Along with useful information about foods that raise, lower, and help with high cholesterol, the author has a number of helpful chapters, such as a list of foods to avoid to immediately begin lowering cholesterol, knowing the tell tale signs of a heart attack, and healthy recipes which will immediately lower your cholesterol levels. Davis' ability to collect such an astounding array of oftentimes obscure information and arrange it in a way that is easy for people of all ages to follow and apply to their lives immediately is itself quite an achievement. More here...

Natural Cholesterol Guide Summary


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Genetic Considerations

Many MI risk factors such as diabetes mellitus, cholesterol levels, and hypertension have genetic contributions. However, family history is an independent risk factor indicating that there are susceptibility genes in addition to those involved in producing identified risk factors are probably involved. Many candidate genes have been investigated. Polymorphisms in the connexin 37 gene, the plasminogen-activator inhibitor type 1 gene and the stromelysin-1 gene have been associated with increased risk, but clear descriptions of genetic contributions remain elusive.

Primary Nursing Diagnosis

Preoperatively, assess the patient's peripheral pulses, taking care to compare one side with the other. Take the patient's blood pressure measurement in both arms, and auscultate for an aortic insufficiency murmur to establish a baseline for postoperative comparison. Also, administer large volumes of intravenous fluids and blood products to maintain circulation until surgery is performed. Surgical procedures vary, depending on the location of the aneurysm. An ascending arch aneurysm may be replaced with an interposition graft, a composite valved conduit, or a supracoronary graft with separate aortic valve replacement. A transverse arch aneurysm is usually repaired with anastomoses and reconstructions. A graft is used to repair descending thoracic and thoracoabdominal aneurysms. Postoperatively, monitor cardiopulmonary states, especially for patients with congestive heart failure (CHF), because beta-blocking agents may worsen CHF. If the patient has hypercholesteremia that cannot be...

Discharge And Home Healthcare Guidelines

The nonsurgical patient is discharged to the home setting. The surgical patient is usually discharged to the home setting if a support system can be identified. An extended-care facility may be required for a short time if a support system is not in place for the patient at the time of discharge. Be sure the patient understands all medications prescribed, including dosage, route, action, and side effects. Provide patients and their families with information about a low-fat, low-cholesterol diet (reduced-calorie if obese). Be sure the patient understands the importance of controlling blood pressure and blood cholesterol levels in the prevention of progression of the atherosclerotic process.

Parallel Group Designs

To illustrate the application of parallel group designs in clinical trials, consider the clinical development of Glucophage. Table 5.2.1 lists three studies of Glucophage regarding evaluation by monotherapy, combination therapy with insulin, and dose response. For the first study (Dornan et al., 1991), the objective was to test the efficacy and tolerability of Glucophage. This study was an eight-month double-blind placebo-controlled trial of Glu-cophage monotherapy in 60 obese patients with NIDDM. This study had a typical parallel group design with a run-in period. After a dietetic review and a one-month run-in period, patients were stratified according to the levels of glycosylated hemoglobin (HbA1C) concentration and randomized to receive either Glucophage or an identical dose of placebo. The starting dose was one tablet (500 mg) daily increased at weekly intervals to three tablets daily after one month. Thereafter the dose was increased by one tablet daily at weekly intervals to a...

Fatty Acid Ethyl Esters As Markers Of Ethanol Intake

Fatty Acid Intake America

The fatty acid composition of serum FAEEs and serum triglycerides from hospital emergency-room patients and plasms non-esterified fatty acids (NEFA) of healthy subjects. The values represent the percent of each fatty acid within either FAEE, triglyceride, or NEFA pools. (From Doyle 1994 with permission.) Fig. 4. The fatty acid composition of serum FAEEs and serum triglycerides from hospital emergency-room patients and plasms non-esterified fatty acids (NEFA) of healthy subjects. The values represent the percent of each fatty acid within either FAEE, triglyceride, or NEFA pools. (From Doyle 1994 with permission.)

Alteration of a Major Fatty Acid Level

An example of oil modification by this technique is the development of high-oleic-acid soybean oil by DuPont through antisense suppressing and or cosuppression of oleate desaturase. The new oil has an oleic acid content of 80 or higher, compared with 24 in normal soybean oil (Liu, 1999). The crop looks so promising that about 50,000 acres were planted in 1998. Because it is more stable, this oil does not require hydrogenation for use in frying or spraying, which reduces processing costs and also avoids the formation of trans fatty acids, which are associated with high cholesterol levels. In addition, this new oil has a longer useful life, which is desirable in the fastfood industry (Riley and Hoffman, 1999). In the case of sunflower, the modified crop is known as mid-oleic sunflower, which has a modified fatty acid profile. It was grown on 100,000 acres in the U.S. in 1998. The seed produces low saturated fat oils with 60 to 75 oleic acid, compared with 16 to 20 in normal oil. This...

Natural Occurrence Of Microbial Polysaccharides In Foods

Bacteria (Streptococcus, Lactobacillus and Lactococcus spp.), and a number of structural studies have recently elucidated the nature of some of these polysaccharides. These and other reports can be found in the reviews of De Vuyst and Degeest (1) and Laws et al. (2). Less is yet known about the relationship between structure and physical properties than is the case for Gram-negative bacterial products such as xanthan and gellan (3). As well as the deliberate addition of microbial polysaccharides to food products to obtain specific properties, there are a number of bacterial fermentations in which polysaccharide is produced and is needed to yield a specific type of product. An example of this can be found in certain types of fermented milk product such as yogurts. In some of these, the production of polysaccharide during bacterial growth is claimed to enhance the product, particularly in respect of the body and texture of the product and in its smoothness and mouth feel. This is...

Cholesterol and Fatty Acids

Huang et al. (1993) cite many studies that demonstrate that n-6 fatty acid are able to reduce the level of cholesterol in the blood serum. The data of Horrocks and Harder (1993) showed that n-6 fatty acids and n-3 fatty acids differ in their mode of action in cholesterol reduction, such that n-6 fatty acids redistribute cholesterol and n-3 fatty acid actually reduces the level of cholesterol. Davis (1992) demonstrated that n-3 essential fatty acids are more effective in reducing cholesterol levels in macrophages than n-6 essential fatty acids, most probably by the differential effect on the enzyme acyl-CoA (cholesterol acyltransferase). However, Horrocks and Harder (1983) indicated that cho-lesterol-esterifying enzymes that incorporate free fatty acids into cholesterol esters without the participation of CoA are also present in the rat brain.

Mechanisms responsible for the overexpression of pai1 in diabetes

Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo (93,94,96,100-103,106). Triglycerides and their constituents (fatty acids) appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro (105,107-109). Liver steatosis is another determinant of elevated concentrations of PAI-1, perhaps indicative of the response of both to derangements in the tumor necrosis factor signaling pathway (110). Insulin and triglycerides exert a synergistic increase in accumulation of PAI-1 in conditioned media when both are present in pathophysiological concentrations (105). Analogous results are obtained with insulin in combination with very low-density lipoprotein-triglyceride, emulsified triglycerides, or...

Nonthiazide Hypocalciuric Diuretics

Indapamide (Lozol) is the first of a new class of oral antihypertensive diuretics, the indolines. In a randomized, prospective study, 75 patients with calcium nephrolithiasis and hypercalciuria were randomly assigned to three different therapies diet and fluid, diet and fluid + indapamide 2.5 mg day, and diet and fluid + indapamide 2.5 mg day + allopurinol 300 mg day 3 , During 3 years of treatment, indapamide caused a 50 drop in urinary Ca excretion. Thus, its hypocalciuric effect was as potent as that of the thiazide diuretics. Relative supersaturations of Ca oxalate and Ca phosphate also decreased by 50 . During the treatment period, the stone rate decreased by 95 in the indapamide group (significantly better than the 64 drop in the diet and fluid group). During indapamide treatment, there were no significant changes in serum glucose, total cholesterol or triglycerides. Serum uric acid increased by 1.0 mg dl and serum K decreased by 0.4 mEq liter after 3 years of treatment with...

Bile Secretion And Gall Bladder Function

Converted into the other lipoproteins. The lipoproteins transport cholesterol and triglycerides throughout the body. Loss of excessive bile acids into the colon produces diarrhea. Bile acids or their degradation products inhibit colonic absorption of sodium and H2O. This results in diarrhea without loss of fat in the stool, if the resynthesis of bile acids can keep up with the loss. In cases of extreme loss, such as after ileal resection, the digestion and absorption of long-chain triglycerides is also impaired and steatorrhea results as well. The steatorrhea can be cured by substituting medium-chain triglycerides for long-chain triglycerides in the diet. Medium-chain triglycerides do not require micelle formation for absorption.

C5L2 an Antiinflammatory Molecule or a Receptor for Acylation Stimulating Protein C3adesArg

As the functional receptor for C3a and ASP C3a-desArg leading to triglyceride synthesis and glucose uptake (Kalant, Cain, Maslowska, Sniderman, Cianflone, and Monk 2003 Kalant, Maclaren, Cui, Samanta, Monk, Laporte, and Cianflone 2005). Based on these observations, downstream signaling of ASP such as the activation of the phospholipase C pathway has been attributed to C5L2. Investigations on patients have been started to associate mutations of this receptor with reduced ASP-stimulated triglyceride synthesis and glucose transport (Marcil, Vu, Cui, Dastani, Engert, Gaudet, Castro-Cabezas, Sniderman, Genest, and Cianflone 2006), and increased plasma levels of triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP (Maslowska, Legakis, Assadi, and Cianflone 2006). In 1987 a partially purified protein fraction has been described which stimulated fatty acid uptake and esterification by human adipocytes and cultured skin fibroblast (Cianflone,...

Procedures For Msms Screening

Long-term therapies for most diseases include low-protein and or low-fat diets. Depending on the respective diseases, carnitine supplementation, coenzyme administration, avoidance of fasting, and treatment of acute episodes with intravenous infusion of glucose may be required. Medium-chain triglycerides are used for some fatty acid oxidation disorders, and sodium benzoate or alternatives are for hyperammonemia of urea cycle disorders.

Artificial Sweeteners

Used in moderation, table sugar (sucrose) can be a part of your diet. However, if you are having problems with glucose control or you are trying to limit your carbohydrate intake (for weight loss or lowering triglycerides), reducing the amount of sugar you eat may be important to you. If this is the case, you have the option of using sweeteners that do not raise blood glucose levels. Aspartame (NutraSweet) consists of two major amino acids, aspartic acid and phenylalanine, which combine to produce a sweetener 180 times as sweet as sucrose. A major limitation is that it is not heat stable, and so it cannot be used in cooking. Saccharin (Sweet 'N Low), sucra-lose (Splenda), and acesulfame potassium (Sweet One) are other sweeteners that can be used in cooking and baking. Fructose is a natural sugar substance that is a highly effective sweetener and only slightly increases blood glucose levels, and it does not require insulin for its metabolism. However, high amounts of fructose do raise...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Data on HRT in postmenopausal women with diabetes are scarce but are of major importance, because these women are characterized by hyperandrogenicity, insulin resistance, and dyslipidemia and are at a higher risk for developing CHD. Evidence from the available data suggest that short-term unopposed oral estradiol has a beneficial effect on glucose homeostasis, lipid profile, and other components of the metabolic syndrome, which may be compatible with a reduced risk of CHD. The addition of a progestogen may attenuate some of these favourable effects. On the other hand, HRT consisting of continuous combined transdermal 17 -estradiol and oral norethisterone, reduces plasma triglycerides and cholesterol concentrations, factor VII activity and von Willebrand factor antigen levels without concomitant changes in adiposity and glycemic control. These effects, allied with favorable effects on CRP and potential beneficial effects on vascular reactivity, suggest that this regimen may hold...

What determines interchangeability for efficacy

Cerivastatin was very effective in reducing LDL cholesterol, but it was taken off the market. In contrast to the other marketed statins, cerivastatin caused rhabdomyolysis in a substantial proportion of patients, especially when given in combination with gemfibrozil. The selective COX-2 inhibitors were introduced for pain relief, especially for patients with a history of gastrointestinal symptoms. Rofecoxib and valdecoxib were recently taken off the market, while celecoxib was allowed to remain.

Primary Hypertriglyceridemia

Triglyceridemia and hypercholesterolemia ensue, whereas in others an isolated elevation of either VLDL or LDL occurs. This variability is thought to be related to the degree of the decreased function of lipoprotein lipase, the enzyme responsible for the hydrolysis of the triglyceride core of both VLDL and chylomicron (1).

Total Lipid Recovery

Most of the organic solvents already mentioned will dissolve the triacylglycerols and free the fatty acids of Figure 3.1. The difficulty in total lipid extraction is twofold (1) Some of the solvents are immiscible with water and (2) some are poor solvents for the polar lipids (mostly phospholipids). The triglycerides may be obvious in fatty streaks or layers, or they may exist in the form of adi-pocytes (fat cells) scattered within muscle tissue. A very small fraction will be found in the cell membrane bilayers, which are mostly phospholipids. It is likely that the latter do not exist in the neat arrangements usually shown but are instead hydrated to some extent because of the affinity for water of both the phosphoric acid and amino acid molecules on the 3-position of the glycerol.

Primary Disorders of LDL Metabolism

Familial Hypercholesterolemia Familial hypercholesterolemia (FH) is a common disorder occurring in 1 in every 500 people in the United States (2). The clinical manifestations include tendinous xanthomatosis most commonly involving the Achilles, the patellar, This disorder is autosomal dominant. Its clinical manifestations are similar to those of FH and include tendon xanthomas and premature coronary artery disease. In this disease, the LDL receptor is normal. However, apo B-100, the ligand for the LDL receptor, is dysfunctional. Consequently, LDL is not cleared readily from the circulation, resulting in elevated LDL cholesterol levels (2). In this disorder, patients readily absorb phytosterols and cholesterol in abnormally large concentrations from the intestine, causing cholesterol levels as high as 700 mg dL, with a predominance of LDL. Tendinous and tuberous xanthomas, premature coronary artery disease, polyarthritis, and a leukocytoclastic vasculi-tis are the most common...

Prevention and Treatment of Diuretic Induced Hypokalemia

The first approach to preventing diuretic-induced hypokalemia is to use the lowest dose possible (Table 1). With regard to thiazide diuretics, the majority of the blood pressure lowering effect is seen at doses of 12.5-25 mg day. At higher doses, further blood pressure lowering is minimal, but rather, metabolic side-effects such as hypokalemia, hyperglycemia, and hypercholesterolemia become more prevalent.

Inhibitors of AGE Production

Conversely, hyperglycemia, which increases oxidative stress, can convert even elevated levels of NO to peroxynitrite, which is deleterious to vascular function (179). A decrease in oxidative stress can restore vascular function rather than increase the NO supply. Prolonged hyperglycemia and hypercholesterolemia both cause a depletion of tetrahydrobiopterin (BH4), an essential cofactor for NOS, resulting in an uncoupling of eNOS and lowered production of NO (180). Studies using both diabetic animal models (113) and hypercholesterolemic patients (112) have demonstrated that tetrahydrobiopterin

Quantitativequalitative abnormalities of lipoproteins

VLDL levels has been attributed to increased hepatic production or decreased clearance of VLDL (111) and may be very significant in the development of arteriosclerosis in diabetes and in women (112). HDL levels in diabetes vary with the type of diabetes and, in some groups, with glycemic control. In type 2 diabetic patients, HDL levels are usually low and do not necessarily increase with improved metabolic control (107,110,113). The low HDL levels are secondary to an increased clearance rate by hepatic triglyceride lipase (114). In type 1 diabetic patients it has been shown that HDL cholesterol levels are low during poor glycemic control and increase to normal or above normal when adequate control is attained (108,110,115). Changes with improved glycemic control are less marked in women than in men (108). In type 1 black diabetic women, little association is observed between plasma lipid levels and glycemic control (115). Abnormalities in LDL lipid composition may also lead to altered...

Integrated Actions Of Metabolic Hormones

Although reesterification of fatty acids can regulate FFA output from fat cells, regulation of lipolysis and hence the rate at which the cycle spins provides a wider range of control. It has been estimated that under basal conditions 20 of the fatty acids released in lipolysis are reesterified to triglycerides, and that reesterification may decrease to 9-10 during active fuel consumption. Under the same conditions,

Effects on Particular Organs or Organ Systems

Mechanisms that impair the release of triglycerides to the blood. Carbon tetrachloride and ethanol are among the substances that can cause this. Necrosis is caused by carbon tetrachloride, which forms free radicals in the liver, as well as by other halogenated hydrocarbons. Cirrhosis is the formation of scar tissue in the liver. It is also caused by carbon tetrachloride, although ethanol is most commonly associated with this condition. Although there is evidence to the contrary, the effect of ethanol may be related to nutritional deficiency associated with alcoholism. Cholestasis is an inflammation of the ducts carrying bile or a decrease in bile flow by other mechanisms. There are many types of liver cancer, and many chemicals are known to cause cancer in laboratory animals. The role of chemicals in human liver cancer is less clear, except for the notable case of vinyl chloride, which is known as a potent cause of angiosarcoma.

Another Structural Insight

Recently, it has been widely reported that the new class of wonder drugs called COX-2 inhibitors exhibit serious cardiovascular side effects, and several of these drugs have been withdrawn from the marketplace. Meanwhile, another class of blockbuster drugs, the statins, may not only be safe and effective in their intended role of lowering cholesterol, but may have a plethora of other potentially valuable properties. Cancer, Alzheimer's disease, dia among the diseases that the statins may ameliorate.21 It has often been said that drugs are discovered in the clinic. In this sense the clinic consists of the patients using these drugs in the general population. Observational studies on the millions of people taking these drugs revealed the problems of COX-2 inhibitors and the additional potential indications for the statins. Another example of this in a much smaller population can serve as an illustration.

Nonsalivary Entangling Secretions

Aphid species in many genera also utilize an entangling secretion as a primary means of defense. In this case the exudate is discharged in response to a confrontation, often hardening to a waxy plaque on an adversary within 30 s. This defensive behavior, which appears to be widespread in the Aphididae, uses tubular secretory organs, the cornicles, on the fifth and sixth abdominal tergites. The secretions, which are dominated by triglycerides, have been characterized in a range of genera, including Aphis, Myzus, Acyrthosiphon, and Therecaphis. The cornicular secretions are clearly more effective against generalized predators (e.g., ants) than they are against specialized predators (coccinellids, nabids). The secretions also contains alarm pheromones, E-fi-faxnesene

Effects Of Nutrition On Individual Growth

Although food availability may not be a limiting factor for growth in some insects, food quality may impose a substantial constraint to larval growth. Differences in food quality also can affect larval growth rates and the ability to complete development and reproduce. Absolute and relative growth rates of the caddisfly Clistoronia magnifica (Trichoptera Limnephilidae) reared on diets differing in quality were significantly higher on a diet rich in triglycerides (conditioned alder leaves plus whole wheat grains) compared with diets of conditioned alder leaves, conditioned alder leaves with a fatty acid mixture, conditioned alder leaves plus hyphomycete fungi, or hyphomycete fungi alone. In addition, only larvae fed the high-triglyceride diet successfully completed development and reproduced. Some insects, however, even in the absence of higher quality food, can maintain a relatively uniform growth rate throughout development by increasing ingestion rates of lower quality food.

Classes of Carbohydrates

These are organic compounds that usually contain a fatty acid or a fatty acid derivative. Lipids are a highly diverse and varied class of compounds soluble in organic solvents. Fat is obtained in the diet from either animal or vegetable sources as triglycerides. Triglycerides are composed of molecules of glycerol and three fatty acids. The fatty acids may be saturated, unsaturated, or contain multiple unsatura-tions (polyunsaturated fatty acids, PUFAs). In addition, lipids contain sterols, ste

Possible Implications Of Observations In Rat In Human Behavior

In classical lipid nutrition for the prevention of atherosclerosis and related diseases, hypercholesterolemia and animal fat were considered to be the major risk factors and high-LA vegetable oils were recommended. Although this recommendation was found to be ineffective (Multiple Risk Factor Intervention Trial Research Group, 1982) and even to be risky for atherosclerosis-related diseases, an increase in the incidence of violent death was observed to be associated with it (Strandberg, 1991 Muldoon, 1990 ). The plasma cholesterol level does not decrease significantly after prolonged dietary recommendations to raise the vegetable oil animal fat ratio (or P S ratio) of food the hypocholesterolemic effect of dietary LA was found to be only transient (Okuyama, 1997, 2000). Therefore, it is not cholesterol that is associated with the increase in the incidence of violent death rather, the increased intake of LA and the elevated n-6 n-3 ratio are likely to be the cause, in view of the...

Oxidation of Fats and Amino Acids

The human body maintains only enough stored glycogen to last about a day. Then it must switch to fats as a fuel. Most fats are stored in the body as triglycerides. Because they are not soluble in water, they must be transported in the blood as lipoproteins. After a fatty meal the concentration in the blood may be sufficient to give it a milky opalescence. Lipase enzymes in the blood or in fatty tissues hydrolyze the lipoproteins to glycerol and to fatty acids bound to blood proteins. The glycerol enters glycolysis after a few steps involving ATP. The fatty acids enter the cell and react with CoA similar to the way pyr-uvate does at the start of the Krebs cycle. The fatty acid-CoA compounds are then transported into the inner compartment of the mitochondria, where a series of reactions split off the last two carbons of the fatty acid, with the CoA, forming acetyl-CoA and a shorter fatty acid-CoA. The process, called beta oxidation, is repeated until the fatty acid has

Pglycoprotein Gene Polymorphisms And Their Implications In Drug Therapy And Disease

Digoxin and higher plasma drug levels. These results, however, were later contradicted by those of other groups. A recent metaanalysis suggested that the C3435T SNP has no effect on the expression of MDR1 mRNA or the pharmacokinetics of digoxin.211 Conflicting data have been reported on the effects of other alleles using various drug substrates, and the controversy seems likely to continue. The differential effects of Pgp polymorphisms on Pgp expression and drug disposition will probably not be resolved until progress is made in standardizing parameters such as sample size and makeup, environmental factors, and the assays used for Pgp protein and mRNA quantification. MDR1 haplotypes, rather than individual SNPs, are also more likely to affect the pharmacokinetics of MDR1 substrates. Two common Pgp polymorphisms (G2677T A and C3435T) may play a role in the differential response to the cholesterol-lowering statin drugs.212 When haplotypes were also considered, a subgroup of female...

Description Medical Diabetes

The beta cells of the pancreas produce insulin and a protein called C-peptide, which are stored in the secretory granules of the beta cells and are released into the bloodstream as blood glucose levels increase. Insulin transports glucose and amino acids across the membranes of many body cells, particularly muscle and fat cells. It also increases the liver storage of glycogen, the chief carbohydrate storage material, and aids in the metabolism of triglycerides, nucleic acids, and proteins.

Primary Disorders of HDL Metabolism

This disorder of HDL metabolism is autosomal recessive and very rare. Patients have a very low HDL level, elevated triglycerides, and low LDL levels. Clinically, the disorder is detected in childhood or early adulthood during a routine physical exam or during assessment of a sore throat because of the typical large orange tonsils. These patients also manifest a peripheral neuropathy, hepatosplenomegaly and premature coronary artery disease (8).

How is Vitamin E Taken up and Distributed in the Body

In man, vitamin E is taken up together with dietary lipids and bile in the proximal part of the intestine with an average efficiency of about 30 . All four tocopherols are taken up equally, suggesting that at this level there is no selectivity. Consequently, a diet rich in y-tocopherol or 8-tocopherol increases the level of y- or 8-tocopherol in tissues, albeit in most tissues a-tocopherol is the predominant form. Since competition between the tocopherols occurs, relative tissue levels of tocopherols are depending on the relative amount of each tocopherol in the diet 19 . The tocopherols are re-assembled together with triglycerides, cholesterol, phospholipids and apolipoproteins into chylomicrons (Fig. 1A). In the course of chylomi-cron lipolysis, a part of the vitamin E is distributed to peripheral tissues, and the liver with the chylomicron remnants captures the other part. Lipoprotein lipase increases the transfer of tocopherol from chylomicrons into skeletal muscle cells 20 . Only...

Impacts Of Solubility On Developability

However, there are some examples of successful drug products on the market with poor-water solubility. One of the examples is Zocor (Simvastatin), a cholesterol lowing product, which is practically insoluble in water. About 68 of 123 oral drugs in immediate-release dosage forms on the World Health Organization (WHO) Essential Drug List have poor water solubility. Similar percentage holds true for the top 200 prescribed oral products in the United States.11

Glucosefatty Acid Cycle

The self-regulating interplay between glucose and fatty acid metabolism is called the glucose-fatty acid cycle. This cycle constitutes an important biochemical mechanism for limiting glucose utilization when alternative substrate is available, and conversely limiting the consumption of stored fat when glucose is available. Fatty acids that are produced in adipose tissue in an ongoing cycle of lipolysis and reesterification may either escape from fat cells to become the free fatty acids, or they may be retained as triglycerides, depending on the availability of -glycerol phosphate (Fig. 1). The only source of -glycerol phosphate for reesterification of fatty acids is the pool of triose phosphates derived from glucose oxidation, because adipose tissue is deficient in the enzyme required to phosphorylate and hence reuse glycerol released from triglycerides. Consequently, when glucose is abundant, -glycerol phosphate is readily available, the rate of reesterification is high relative to...

Interactions Of Responding Systems

Although a hormone may trigger an overall cellular response by affecting some fundamental rate-determining reaction, several cellular processes may be affected simultaneously. Hormonal effects exerted at several locales within a single cell reinforce each other and sum to produce the overall response. Let us consider, for example, just some of the ways insulin acts on the fat cell to promote storage of triglycerides It inhibits breakdown of already formed triglycerides.

Gender Ethnicracial And Life Span Considerations

MI is the single largest cause of death among American men and women, including white, African American, and Hispanic Latino populations. The risk of MI increases with age, and it occurs most commonly in people older than 45 years of age. MIs also occur in young adults, such as individuals who use cocaine, those who are insulin-dependent diabetics, and those who have hypercholesterolemia and a positive family history for early coronary disease.

The Future Is Here Functional Foods

If your breakfast this morning included calcium-fortified orange juice and toast made with folate-enriched flour, you are a consumer of functional foods. Just what is a functional food As the fastest growing category of new food products, these are foods or food components to which manufacturers have added ingredients that are known or believed to promote health and prevent disease (see Chapter 4, What Do the Terms Fortified and Enriched Mean page 92). Although the name functional foods is new, the concept is not when it was discovered in the early part of the 20th century that some thyroid disease was caused by a deficiency of the mineral iodine, manufacturers began enriching table salt with iodine. Since that time, we have also seen vitamin D-for-tified milk, breakfast cereals fortified with a variety of vitamins and minerals, and the addition of preservatives that are themselves antioxidants to almost all processed foods (see Chapter 3, Cholesterol-Lowering Margarine, page 66). The...

The Presence Of Fatty Acid Ethyl Esters In Vitro And In Vivo

The first description of in vitro enzymatic synthesis of fatty acid ethyl esters came from Margolis in 1962 (Margolis, 1962). In experiments with adipose tissue microsomes, he showed that glycerol, ethanol, and several other alcohols form esters with 14C-palmitate when the alcohol is added in millimolar concentration. The esterification of these alcohols required the presence of CoA and ATP or of 14C-palmityl-CoA. Intrigued by this observation, Goodman and Deykin injected rats with 14C-radiolabeled ethanol and tentatively identified long-chain fatty acid ethyl esters in total-body lipid extract (Goodman, 1963). In 1965, Newsome and Rattray reported that porcine pancreatin contained a source of enzyme activity to esterify ethanol with fatty acids (Newsome, 1965). Patton and McCarthy in 1966 observed that goat milk converted alcohol and fatty acids into ethyl esters in vitro (Patton, 1966). A prominent spot was observed on the thin-layer chromatography autoradiogram between the solvent...

Influence of n3 PUFAs on Acquisition and Distribution of Body Fat Food Intake and Body Weight

Pufa Obesity

Maintained male Wistar rats on a lard or MaxEPA (high in long-chain n-3 PUFA) diet in which the fat content of the diet comprised 40 of the energy. By 5 wk, fat in epididymal and perirenal tissues, as well as plasma triglycerides, were lower in the MaxEPA group. Given that nearly 100 of the cell volume of adipose tissue is triglycerides, factors that influence their synthesis and breakdown are crucial. It has been suggested that n-3 PUFAs restricts adipose tissue growth by limiting the amount of triglyceride in each cell (Parrish et al., 1991). Altered expression of genes encoding lipogenic (fatty acid synthase and lipoprotein lipase), lipolytic (hormone sensitive lipase), and glyceroneogenic enzymes because of ingestion of n-3 PUFAs appear to be important in reducing body fat stores.

In Vivo Applications Liver Transduction

The potential of liver-directed, HDAd-mediated gene therapy was investigated for the phenotypic correction of hypercholesterolemia in the apolipoprotein E-deficient mouse model. 6 Apolipoprotein E, a 34-kDa plasma glycoprotein, is a component of all plasma lipoproteins except low-density lipoprotein (LDL) and plays a major role in lipoprotein catabolism by acting as a ligand for the LDL-receptor (LDLR) and the LDLR-related protein for transport of excess cholesterol from the peripheral tissues to the liver for excretion. The apoE_ _ mouse is an excellent model for cardiovascular disease because they develop severe hypercholesterolemia and atherosclerotic lesions similar to those found in humans. Chan and coworkers investigated correction of hypercholesterolemia in apoE_ _ mice with either a FGAd or a HDAd expressing apoE. 6 Injection of apoE_ _ mice with FGAd resulted in an immediate rise in plasma apoE levels and a concomitant drop in plasma cholesterol levels to within normal range....

Byproducts of irradiation

Result from the breakdown of triglycerides amino acids that make up proteins and compounds (hydrocarbons) commonly found in the waxy coverings of fruits such as apples, pears, and berries. Others are fatty compounds identical to those found from cooking meat by common methods such as grilling. The other 10 of radiolytic compounds are chemically very similar to natural components in food. The chemistry of irradiation is very predictable, and the products of an individual component such as proteins are not affected by the type of food or other food components present. Radiolytic products have been critically tested for toxicity and no evidence of hazards has been found.

Management of dyslipidemia Rationale

Prior to the introduction of statins or HMG CoA-reductase inhibitors, three major clinical trials attempting primary prevention of coronary artery disease through the use of other LDL-lowering medications were conducted. The World Health Organization (WHO) Cooperative Trial, using clofibrate to reduce serum cholesterol levels (16), documented a 20 reduction in first major coronary events and a 25 reduction in nonfatal myocardial infarctions. However, the all-cause mortality rate was significantly higher in the clofibrate-treated group, raising concerns regarding safety. Another trial, the Lipid Research Clinics Coronary Primary Prevention Trial, demonstrated the efficacy of cholestyramine in reducing the number of coronary artery disease deaths (-24 ) and the number of nonfatal myocardial infarctions (-19 ), with no significant rise in the all-cause mortality (17). In the later Helsinki Heart Study in 1987 (18), gemfibrozil was shown to be efficacious in the primary prevention of...

Autosomal Dominant Inheritance

There are hundreds of medical conditions due to autosomal dominant alleles, most of them very rare. They include neurodegenerative disorders such as Huntington's disease, a variety of deafness syndromes, and metabolic disorders such as familial hypercholesterolemia (affecting blood cholesterol levels) and variegate porphyria (affecting the oxygen-carrying porphyrin molecule). Table 1 lists some other examples.

Nongenomic Actions Extranuclear Actions

Several tissue- and TR isoform-specific compounds have been developed as potential treatments for hypercholesterolemia, obesity, and heart failure reviewed in 96 . In the development of these compounds it is attempted to use information on tissue-specific uptake of the compound. One of the initial compounds was investigated in mice, who subsequently had lower serum cholesterol levels without cardiotoxicity. Recently, several other TH analogs have been described that have compared to TRa. Since thyroid hormone receptors in the liver, isoform-selective affinity for TRp is approximately 90 TRp, and in the heart mostly TRa, these isoform-selective compounds may serve as novel agents to lower serum cholesterol with minimal cardiotoxicity. Recently, KB141 was shown to be a potential treatment for obesity by decreasing body weight via stimulation of metabolic rate and oxygen consumption.

Xiimelting And Crystallization

Studies by Hernqvist (1984) shed light on the structure of triglycerides in the liquid state and how this affects crystallization. On the basis of x-ray diffraction and Raman spectroscopy studies, he suggested a gradual decrease in size with increasing temperature of the melt (Figure 2.7). The order in the melt is constant even at 40 C above the melting point. The order is related to chain length a long chain is more disordered at the methyl end-group plane than a short one. When the temperature is decreased, the lamellar units increase in size until crystallization occurs (Figure 2.8).

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women.

Role Of Fatty Acid Oxidation In Other Diseases

Influence the development of these more chronic disease processes. They found that the BALB cByJ mice became significantly heavier and had significantly higher total serum cholesterol, HDL cholesterol, and triglyceride concentrations in the fed state than C57BL 6J mice. These authors did not mention the fact that these mice have SCAD deficiency. As more is learned by genetically manipulating lipid metabolism in mouse models, we can more fully understand the roles aberrant fatty acid metabolism plays in these complex, chronic disease processes.

Abnormalities in the fibrinolytic system

Impaired fibrinolytic activity is characterized by low t-PA activity and high PAI-1 antigen and activity. Studies in man have shown that t-PA antigen concentration (associated with high PAI-1 and low basal or stimulated t-PA activity) may be high in subjects with preclinical atherosclerosis and a marker for the development of coronary and cerebrovascular events (276,277). Furthermore, t-PA antigen has been found to have a higher predictive value for mortality in patients with established CAD than cholesterol, triglycerides, fibrinogen, blood pressure, diabetes, or smoking (278). Like in nondiabetic subjects, impaired fibrinolysis is an independent risk factor for MI in diabetic subjects (279,280).

Maternofetal Conversion in Primates

To quantitatively estimate the relative contributions of the mother and fetus to supplying fetal brain DHA requirements, we studied the metabolism of LNA* and DHA* in pregnant animals, administering doses to the maternal or fetal bloodstream. Pregnant baboons consumed a LCP-free diet for approximately 8 wk prior to 13C tracer dose, to minimize effects of uncontrolled intake of LCP incidentally included in fishmeal of commercial primate diets. At the beginning of the third trimester (140 d of gestation age dGA , term 182 d), a U-13C -LNA or U-13C -DHA dose as nonesterified fatty acid in a soy oil emulsion was given intravenously to the pregnant animals or the fetuses. When fats are consumed, lipoprotein lipase located at the maternal side of the placenta cleaves LCP esterified in the triglycerides or phospholipids of lipoproteins into free fatty acids (Dutta-Roy, 2000 Stammers, Stephenson, Colley, & Hull, 1995), which can then bind to fetal plasma proteins and be transported to fetal...

Clinical manifestation

As knees, elbows, or buttocks may coalesce to form multilobated tumors associated with hypercholesterolemia and increased levels of LDL, with familial dysbetalipopro-teinemia and familial hypercholesterolemia or with secondary hyperlipidemias (e.g., nephrotic syndrome, hypothyroidism) Tendinous xanthoma variant slowly enlarging subcutaneous nodules around tendons or ligaments, often over extensor tendons of the hands, the feet, and the Achilles tendons sometimes occurs after trauma associated with severe hypercholesterolemia and elevated LDL levels, particularly in the type IIa form, or secondary hyperlipi-demias such as cholestasis Eruptive xanthoma variant sudden onset of crops of small, pruritic, red-yellow papules on an erythematous base, most commonly over buttocks, shoulders, and extensor surfaces of extremities may spontaneously resolve over weeks associated with hyper-triglyceridemia, particularly with types I, IV, and V (high concentrations of VLDL and chylomicrons) or with...

Considerations For Future Intervention Trials

The long history of clinical studies in cardiovascular diseases, infant nutrition, and other illnesses have yielded valuable lessons that can help to form the design of future studies of psychiatric disorders. Baseline measurements are essential, as some subjects may enter the study with high tissue concentrations of EPA and DHA and supplementation may produce little additional effect. Biological markers are the most accurate measure of fatty acid status, but a simple dietary questionnaire may be able to screen out subjects with a high omega-3 intake. The baseline diet should be standardized at a low seafood and omega-3 intake. If subjects in the placebo group begin to eat more fish because of their excitement in being part of the study, then treatment effects may be difficult to detect. Consideration should be given to the course of their illness and number of failed treatments. For example, it may be difficult to detect treatment differences among subjects who are treatment...

Fatty Acid Ethyl Esters As Fatty Acid Supplements

Supplementation and with the introduction of FAEE capsules for oral intake, there were a number of studies to evaluate ethyl ester absorption from the gastrointestinal (GI) tract. In 1991, Nordoy et al. reported that ethyl esters and triglycerides were equally well absorbed from the GI tract in human subjects (Nordoy, 1991). In 1992, Yamazaki et al. (Yamazaki, 1992) infused emulsions of ethyl eicosapentaenoate (ethyl EPA) into rat veins and demonstrated that the EPA content in the phospholipids of a variety of organs substantially increased. It has also been shown that treatment of normal volunteers with oral n-3 FAEE, with approximately 3 g of ethyl EPA plus ethyl docosahexaenoic acid (ethyl 22 6) per day, results in a marked accumulation of the fatty acids from these ethyl esters in the plasma and in cell lipids within 6 wk (Marangoni, 1993). Harris et al. conducted a randomized, placebo-controlled, double-blind, crossover trial in which 10 mildly hypertriglyceridemic patients were...

Nitrogen Removal During Wastewater Treatment

B Calculated for triglycerides containing glycerol plus 3 mol palmitic acid. c Calculated for polyalanine and reaction of ammonia to (NH4)2CO3. d at standard conditions b Calculated for triglycerides containing glycerol plus 3 mol palmitic acid. c Calculated for polyalanine and reaction of ammonia to (NH4)2CO3. d at standard conditions

Application To Triglyceride Crystallization

Turning at last to foods, the rates at which oils crystallize and undergo polymorphic transitions are important in determining texture and physical stability in a variety of food products (Larsson, 1982). Edible oils consist almost entirely of triglycerides, with small amounts of mono- and di-glycerides and other minor components (Swern, 1979, Chapter 1). Hence attention has been concentrated on crystallization of triglycerides (TG's).

HMGCoA reductase inhibitor Atorvastin

Statins act by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the first committed enzyme of the HMG-CoA reductase pathway. Sen et al. found that statins retard the progression of retinopathy in patients with diabetes mellitus and hypercholesterolemia (Sen et al., 2002), whereas other studies have reported that statins limit the severity of hard exudates and subfoveal lipid migration in CSME (Gordon et al., 1991 Gupta et al., 2004).

Low Carbohydrate Diets

Carbohydrate, high-protein diet had indeed lost more weight than the people on the low-fat diets, but by twelve months both groups had lost the same amount of weight. A significant proportion of subjects in both groups dropped out of the study by one year (up to 50 percent in some studies). Since the studies were for one year only, it is hard to determine if one diet or the other would be detrimental to health. What was noted was that those on the Atkins diet had lower triglycerides and higher HDL cholesterol, whereas those on the low-fat diet had lower LDL cholesterol levels. There are no studies, however, that look at long-term benefits or hazards of the low-carbohydrate, high-protein diets, and so the ADA does not recommend them.

Methods of DHA Administration and Dietary Regimen

Docasahexaenoic acid was administered orally either as the ethyl ester or as the triglyceride. The DHA ethyl ester was supplied by the Charleston Laboratory through a grant from the Fish Oil Test Materials Program (NIH ADAMHA DOC). This material is no longer available at this time. The triglyceride preparation is supplied by the Martek Bioscience Corporation, as a product referred to as DHASCO ARASCO. The DHASCO supplies DHA, and the ARASCO provides arachidonic acid. The triglycerides contain 47 DHA and 46 arachidonic acid. They are administered as a microcapsule that can be sprinkled on food. The daily dosage of the ethyl ester varied between 100 and 500 mg, depending on the age and degree of DHA deficiency (Martinez, 2000). The initial dose of DHASCO ARASCO was 100 mg kg. Dosages are adjusted on the basis of plasma DHA and arachidonic acid levels, with the aim of maintaining these levels as close to normal as possible. Martinez does not recommend pharmacological supplementation with...

Other Types Of Diabetes

If you have limited beta cell function, using prescription medicines that either decrease insulin effectiveness and or further decrease beta cell function can cause diabetes. For example, steroids such as prednisone and dexamethasone, which are used to treat inflammation, can cause blood glucose to rise in some people. Niacin, a drug used to lower triglyceride levels and raise HDL cholesterol levels, reduces insulin effectiveness and can cause an increase in blood glucose.

Impaired glucose tolerance is a disease

Triglycerides prevent or delay the progression of IGT to type 2 diabetes underscores the need for early diagnosis (1). The accelerated heart disease in IGT probably stems from the presence of insulin resistance and its associated metabolic syndrome, which are defined in Table 2 according to the NCEP ATP III report (1). Three of five elevated factors, which are easy to measure, constitute the metabolic syndrome. Certain components of the syndrome, such as low HDL, elevated triglycerides, and hypertension, are well-known risk factors for cardiovascular disease. Other components that are less commonly measured in the clinical setting, such as elevated small, dense LDL cholesterol (the moiety that is more susceptible to oxidation) and elevated levels of the prothrombotic factor plasminogen activator inhibitor-1 (PAI-1), correlate with cardiovascular events and mortality (19). Whether coronary artery disease risk factor goals should be as stringent in IGT as in type 2 diabetes is unknown....

Effects of HRT on Lipids in Women With Diabetes

Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in triglycerides with oral CEE (149), although one showed a greater increase among women with diabetes Transdermal estradiol combined with oral norethisterone significantly decreases total cholesterol and serum triglycerides without significantly affecting LDL-C and HDL-C Regarding Lp(a), no significant differences were found among the groups studied in the NHANES III survey. However, in a randomized controlled study combined continuous HRT (CEE + MPA) has shown beneficial effects on Lp(a) in postmenopausal...

HRT and Genetic Factors

Thus the estrogen associated risk for thrombosis may be increased in the presence of the prothrombin 20210 G A variant, the factor V Leiden mutation or platelet antigen-2 polymorphisms (95-97). A common sequence variation of the ER gene is associated with the magnitude of the response of HDL cholesterol levels to HRT in women with coronary disease (19). The same ERP genotype is also related to changes in the levels of SHBG, another index of estrogen action (95). It is also interesting that in the HERS trial high levels of Lp(a), which is largely genetically determined, were an independent risk factor for CHD events in the placebo group. HRT lowered Lp(a) levels and the cardiovascular benefit of HRT was significantly related to the initial Lp(a) levels and the magnitude of the reduction in the level (98). It appears therefore, that genetic factors may also contribute to the net clinical effect of HRT regarding CVD in postmenopausal women.

Diabetes and fibrinolysis

Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95) that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96) and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched subjects who had not experienced any manifestations of overt CAD (97). We found that impaired fibrinolysis in subjects with type 2 DM, not only under baseline conditions but also in response to physiological challenge, was attributable to augmented concentrations in blood of circulating PAI-1. Furthermore, obese diabetic subjects exhibited threefold elevations of PAI-1 in blood compared with values in nondiabetic subjects despite tissue-type plasminogen activator (t-PA) values that were virtually...

Angiotensin Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been shown both to improve endothelial function and to reduce the development of atherosclerosis in various animal models of hypercholesterolemia (192,193), independent of its BP-lowering effect. Similarly, the Heart Outcomes Prevention Evaluation (HOPE) study has demonstrated the utility of the ACE inhibitor ramipril in preventing cardiovascular events in diabetics (194) although the mechanism of this effect remains obscure. Clinical trials have demonstrated that the ACE inhibitor quinapril improved endothelial function in nondiabetic patients with CAD (195). Studies evaluating the effect of ACE inhibitors on type 1 diabetic subjects have resulted in conflicting conclusions. Two studies have demonstrated that ACE inhibitors have no effect on vascular function in patients with type 1 DM, even after 6 months on the drug (196,197). However, O'Driscoll and colleagues found improvement in endothelial function by ACE inhibition in...

Diabetes and Insulin Resistance

Although not entirely known, the cellular and molecular mechanisms linking adiponectin to improved insulin sensitivity are also likely multifactorial. In rodents, adiponectin administration enhances insulin-stimulated glucose uptake into fat and skeletal muscle cells (49-51). By increasing fatty acid oxidation, adiponectin can also lower circulating free fatty acids (FFAs), which may improve insulin action (51,52). Another important function of adiponectin is enhancement of insulin-induced suppression of hepatic glucose production (53,54). By generating nitric oxide (NO) formation, adiponectin may also augment vascular blood flow to promote glucose uptake (55). Taken together, all these effects could explain why giving adiponectin to mice on a high-fat and high-sucrose diet will induce weight loss and reduction in FFA, triglycerides, and glucose levels (56).

Guidelines for the Treatment of Dyslipidemia

With the recent knowledge regarding the efficacy of therapy with statins, the new NCEP recommendations evolved (Table 5). In the highest risk category, the NCEP recommends that both lifestyle modifications and drug therapy be initiated at diagnosis if the baseline LDL-C exceeds130 mg dL. However, LDL-C levels between 100 and 129 mg dL may necessitate either intensification of lifestyle modification and or initiation of drug therapy at the discretion of the provider. Subjects in the intermediate-risk category are divided into two further subgroups, one with the 10-yr risk of 10-20 and the other with a 10-yr risk of less than 10 according to the Framingham risk stratification criteria. In the first subgroup, the NCEP recommends lifestyle modification for the initial 3 mo and later adjunctive drug therapy if the LDL-C level remains above 130 mg dL. In the other subgroup, lifestyle changes should be instituted with a later addition of drug therapy if LDL-C of less than 160 mg dL is not...

Materials And Methods

Case report The patient was first described by Niezen-Koning et al.5 She presented at 36 hours of age with sudden cardiorespiratory insufficiency and extreme hypogly-caemia. Despite treatment with low-fat diet supplemented with medium-chain triglycerides and carnitine she died at 24 month of age.

Consequences of Diuretic Induced Hypokalemia

First, hypokalemia can raise blood pressure by a mean value of 5-7 mm Hg. This hypertensive response is reversible when oral potassium supplements are given to correct the diuretic-induced hypokalemia in patients on a constant diuretic dose. Second, hypokalemia has been linked to an increased incidence of strokes independent of other cardiovascular risk factors. Other complication of hypokalemia include the development of insulin resistance and hypercholesterolemia.

Testosterone Treatment

Safe and effective androgen replacement therapy (ART) can be provided through the use of intramuscular long-acting testosterone esters, transdermal patches, or transdermal testosterone-containing gel (Table 3). Oral androgen replacement should be avoided because of the consistently deleterious effects of these preparations on LDL and HDL cholesterol levels and (less commonly) hepatic function.

Suketu Shah md Alina Gavrila md and Christos S Mantzoros md

Our understanding of the function of fat cells has changed dramatically with the realization of the endocrine function of adipose tissue. Initially thought to serve only as a repository for energy via storage of triglycerides, adipocytes are now known to secrete a variety of proteins with diverse metabolic functions. These proteins include leptin, TNF-a, plasminogen activator inhibitor-1, acylation-stimulating protein, resistin, and adiponectin (1,2). Adiponectin has received much attention for its putative role in diabetes and CVD. Besides being associated with the development of diabetes, it may also have a direct role in modulating inflammation and atherosclerosis and thereby be one of the factors that links obesity to CVD.

Marybeth Howard and William J Welch 1 Introduction

Defects in protein folding constitute the basis of many genetic diseases cystic fibrosis, alpha-1 antitrypsin deficiency, familial hypercholesterolemia, and congenital nephrogenic diabetes insipidus, to name but a few (see Table 1 for a complete list). In each of these, point mutations or deletions result in a protein product that fails to achieve its properly folded state. For example, in the case of the cystic fibrosis transmembrane conductance regular protein (CFTR), the most common mutation in patients is the loss of a single phenylalanine residue (at position 508) within a polypeptide of 1480 amino acids (1). This seemingly minor alteration results in the newly synthesized CFTR protein being unable to fold properly and traffic to its proper destination at the plasma membrane (2). Instead, the vast majority of the mutant protein is retained at an early point in its maturation pathway and over time is targeted to a degradative pathway (3-5). As a consequence, cells expressing the...

Influence of Omega3 PUFAs on Body Fluid and Sodium Homeostasis

The above-described homeostatic functions are, in large part, dependent on proper neural functioning and the n-3 PUFAs are crucial to neural function. Receptor-driven processes are also crucial to these homeostatic functions. n-3 PUFAs can influence mechanisms known to be involved in body fluid homeostasis. Vaskonen (1996) showed that supplementation of a high-sodium (6 ) diet with n-3 PUFA-rich fish oil increased the ability of stroke-prone-spontaneously hypertensive rats to excrete sodium and prevented the increase in blood pressure and water intake normally caused by the ingestion of 6 NaCl. Fish oil has also been shown to attenuate the increase in blood pressure caused by subcutaneous infusion of ANG II in normoten-sive rats (Hui, St.-Louis, & Falardeau, 1989). In normotensive humans (Kenny et al., 1992), ingestion of n-3 PUFAs (including 1200 mg d DHA and EPA) for 7 days decreased plasma triglycerides and attenuated the increase in vascular resistance caused by ANG II. The n-3...

Public Patient Outcomes

Significantly advancing the care of patients (e.g., statins in hypercholesterolemia in the 1990s). More untreatable diseases are finding amelioration or improvement through product innovation over the past 20 years (e.g., HIV infections with new classes of antiviral drugs, anemia of kidney disease and cancer with epoietin alfa, and enzyme deficiency diseases such as Gaucher disease with enzyme replacement). A novel product choice has been created because of its unique mechanism of action different from existing products, altering a key newly identified pathophysiologic process for a disease (e.g., aromatase inhibitor Arimidex or oncogene inhibitor Herceptin for breast cancer), or a better side effect profile has been achieved (e.g., Nonsteroidal anti-inflammatory drugs for arthritis versus aspirin). The new product achieves patient care improvement with higher efficacy over prior therapy, becoming a clinically superior or even best-in-class product (e.g., Crestor as a statin for high...

Genetic Susceptibility to Complications

As mentioned above, diabetes is associated with complications involving the eyes, kidneys, blood vessels, and heart. However, not all individuals with diabetes develop these complications. There is increasing evidence that there are genes other than those that increase susceptibility to developing the disease that may influence susceptibility to developing its complications. These genes are not yet identified, but they are likely to interact with other known risk factors for complications, including poor blood-sugar control and increased blood-pressure and blood-cholesterol levels. see also Complex Traits Disease, Genetics of Gene and Environment Gene Discovery Immune System Genetics Mitochondrial Diseases.

Biology and Atherosclerosis

Consistent with the effects seen in macrophages, PPAR-y agonists repress inflammatory cytokine production in T-lymphocytes (42). In ECs, PPAR-g may decrease adhesion molecule expression although the results are variable (43,44), pointing out a limitation of a field that has depended heavily on synthetic agonists as experimental tools, with all the attendant concerns of pharmacological studies physiological relevance, receptor dependence, dose dependence, and toxicity effects to name a few. One example of the potential complexities involved is evident in the relationship between PPAR-y ligands and plasminogen activator inhibitor 1 (PAI-1) levels. Several reports indicate PPAR-y ligands may increase expression of PAI-1, a pro-coagulant, pro-atherosclerotic response. Other laboratories find a PPAR-y-mediated repression of PAI-1 (45-47). Others report inhibition of PAI-1 expression (48). In humans, PPAR-y ligands clearly appear to decrease circulating PAI-1, although this may be a...

Rosiglitazone And Pioglitazone

They usually take a few days to work, so you should not expect glucose levels to fall for at least a week or two. The medicine does depend on having enough insulin to be effective. In addition to their glucose-lowering effect, thiazolidinediones lower triglycerides and free fatty acid levels and raise total cholesterol, LDL cholesterol, and HDL cholesterol. Pioglitazone, when compared to rosiglitazone, is more effective in lowering triglycerides and raising HDL cholesterol. It also does not raise LDL cholesterol as much as rosiglitazone does. Since lipid abnormalities are associated with heart disease, it has been proposed that the lipid changes seen with these drugs (especially pioglitazone) might be beneficial. In small research studies these drugs have been shown to prevent the reblockage of coronary arteries after they have been opened with a procedure called coronary angioplasty. These medicines also seem to help fatty liver, an important abnormality found in many people with...

R Common to both approaches

Many groups have found it useful to work backwards through the development and approval process from proposed optimal and minimal package inserts, in an effort to better define the studies that may be needed to support early clinical trials and possible regulatory questions (Fig. 4.21). The major label claims involve five areas noted in the slide and drive at least the five noted aspects of development. As an example, consider the development of a new drug for a cancer indication. What cancers could be treated How will the drug be used clinically (standalone or adjunctive therapy, first-line treatment or salvage treatment, etc.) Are there patient subsets that may respond differently Are there certain toxicities of existing drugs to avoid or not exacerbate How will the drug be administered (oral, intravenous, subcutaneous, etc.), and for how long (a few minutes, days, months, years) How large do phase III trials need to be and what is the approvable end point Answers to these questions...

Alternative Therapies to Hormone Replacement Therapy

Tibolone is a steroid hormone with a progestogen-like structure that is converted to estrogenic and androgenic derivatives in vivo. It improves menopausal symptoms and bone density and potentially has fewer side effects than conventional HRT. Limited human observational data on the cardiovascular effects of tibolone indicate that it reduces triglycerides and Lp(a) levels but also HDL and there is a suggestion that tibolone may not increase thrombotic risk (105). We must await data from clinical trials on definite clinical end-points to establish the vascular effects of tibolone.

Interpretation of Banding Patterns

Membrane lipids can be separated by high-performance thin-layer chromatography (HP-TLC) as phospholipids, free fatty acids, monoglycerides, diglycerides, triglycerides, and cholesterol esters (4). Analysis of the total lipid extract by HP-TLC allows the determination of whether cell lipids are intact or hydrolyzed. The presence of hydrolyzed lipids in a sample, e.g., phospholipids, does not allow the analysis of phospholipid-bound fatty acids. Fatty acid methyl esters prepared following tranesterification of glycerolipids, and, in particular, AA and DHA, can also be analyzed by HP-TLC (see Fig. 1) (4). This provides a rapid quantitative test for the determination of the AA DHA ratio by HP-TLC reflectance spectrodensitometry. However, since co-migration of fatty acid methyl esters by HP-TLC with the corresponding standards does not guarantee that the observed bands on the HP-TLC plate correspond to those fatty acids, the use of gas chromatography mass spec-trometry (GC MS) is required...

Peroxisome Proliferator Activated Receptora Key Regulator of Fatty Acid Oxidation

PPAR-a is expressed in heart, liver, kidney, and skeletal muscle in which it plays a central role in the regulation of lipid, and especially fatty acid, metabolism (16). PPAR-a target genes participate in the conversion of fatty acids to acyl-coenzyme A derivatives, peroxisome P-oxidation, and apolipoprotein expression (A1, AII, and CIII) (10,17). Reminiscent of the story of PPAR-y, fibrates in clinical use for lowering triglycerides and raising high-density lipoprotein (HDL), namely gemfibrozil (Lopid) and fenofibrate (TriCor), were found to be PPAR-a agonists (18). Many insights into PPAR-a have come from the study of PPAR-a-deficient mice (19). For example, these mice lack

Results And Discussion

To elucidate more of the so far not fully understood mechanisms behind the effect of treatment with the thia fatty acids, we compared the effect of treatment with thia acids with the sulphur in different positions (Table 1). The main difference between these 16 carbon (17 including the sulphur) fatty acids is their availability for mitochondrial P-oxidation. As already mentioned TTA is blocked for P-oxidation, but can enter the mitochondria, as it is substrate for CPT-I and CPT-II. However, 5-S, 7-S and 9-S can both enter the mitochondria and undergo 1, 2, or 3 cycles of P-oxidation respectively, before they are metabolised into chain-shortened 3-thia fatty acids which cannot be P-oxidised. Evidently, the metabolised forms of 5-S, 7-S and 9-S will accumulate in the mitochondria. In agreement with earlier findings TTA administration lowered plasma triglycerides, 5-S tended to lower plasma triglycerides, but 7-S and 9-S did not effect the plasma triglyceride levels (data not shown). As...

Structural Abnormalities In Type 1 And Type 2

Primary demyelination is rare in type 1 DPN of the BB Wor-rat, but somewhat more common in both human and experimental type 2 DPN (1,31). The reason for this is not well known, although more common comorbidities in both human and experimental type 2 diabetes such as hypercholesterolemia and triglyceridemia have to be considered.

HMG CoA Reductase Inhibitors

Large clinical trials have determined that hydroxymethylglutaryl-coenzyme A reductase inhibitors ( statins ) significantly reduce cardiovascular morbidity and mortality. Furthermore, lipid-lowering therapy has been shown to improve endothelial function in several studies (204,205). Attempts to ameliorate the impaired endothelium-dependent vascular relaxation that occurs in diabetic patients with dyslipidemia are few and the results mixed. Impaired endothelium-dependent vasodilation in patients with type 2 DM with dyslipidemia has been reported to improve with fibrate therapy (206) (which lowers the serum triglyceride level) but not with simvastatin (206,207).

Does blood pressure lowering predict clinical benefit

Favorable changes in a surrogate marker are sometimes insufficient to recommend full approval and widespread use of the first drug of a particular class. Clinicians and regulatory agencies prefer to see trial evidence of event reductions. When simvastatin (Zocor) was shown to reduce total and LDL-cholesterol, the FDA approved the drug, but asked for outcome trials. When the first large simvastatin trial, 4S,6 showed a convincing reduction in all-cause mortality in coronary patients, use of the drug increased markedly. It is appropriate that the clinical criteria for accepting the first drug of a class are the Cerivastatin (Baycol) was introduced as a potent lipid-lowering agent, and promoted as another statin. Many were led to believe that it was interchangeable with the other approved statins, which had very positive event and safety data. By lowering the cost of the drug compared to the other brandname statins, the manufacturer of cerivastatin succeeded in gaining modest market...

How is the harm of a treatment documented

The most commonly prescribed drugs can be evaluated prior to marketing. In 1997, the FDA approved mibefradil (Posicor) for marketing in the U.S. The product was withdrawn within one year, after multiple serious drug interactions were documented, the most important one with simvastatin (Zocor).

Polycystic Ovary Syndrome and Cardiovascular Risk

Women with PCOS have higher serum triglycerides, total and LDL cholesterol and lower HDL cholesterol levels than weight-matched regularly menstruating women (190). These findings however, vary and depend on the weight, diet and ethnic background. In a large study of non-Hispanic white women, elevated LDL-C was the predominant lipid abnormality in women with PCOS (191). An additional parameter contributing to the elevated cardiovascular risk is hypertension. Obese women with PCOS have an increased incidence of hypertension and sustained hypertension is threefold more likely in later life in women with PCOS (192). It is not clear whether this increase in hypertension is because of the PCOS status, obesity or both. PAI-1 concentrations in blood are higher in women with PCOS as compared to those not affected. PAI-1 levels have been shown to be positively correlated with triglycerides, basal insulin and abdominal obesity (193). It was shown that impaired fibrinolysis and particularly the...

High Fat Diets and Obesity Possible Influence of n3 PUFAs

The peptide hormone insulin is produced in the pancreas and secreted in proportion to the degree of adiposity. Similar to leptin, insulin levels are correlated with amount of abdominal fat (Porte et al., 1998 Woods et al., 1996 Woods, Figlewicz Lattemann, Schwartz, & Porte, 1990 Woods et al., 1998). It is transported into the brain where it acts to decrease food intake and body weight (Schwartz, Figlewicz, Baskin, Woods, & Porte, 1992 Woods et al., 1996). High insulin resistance is a characteristic of obesity, hypertension, and non-insulin-dependent diabetes mellitus. There is an inverse relationship between insulin action and triglyceride content. With the ingestion of fat, insulin secretion is increased. Insulin stimulates fatty acid synthase, an enzyme that catalyzes all reactions involved in lipogenesis, and thereby results in the accumulation of triglycerides (Sul, Latasa, Moon, & Kim, 2000). Monounsaturated fatty acids (such as oleate) and saturated fatty acids (such as...

Clinical Significance

Like the adverse effects of thiazides on glucose metabolism, their effect on plasma lipids is reversible. Therefore, discontinuation of thiazides and use of alternative agents which either lower (e.g., ACE inhibitors, calcium channel blockers) or do not change plasma cholesterol should probably be used for treatment of hypertension in patients with preexisting hypercholesterolemia or combinations of other risk factors such as diabetes, left ventricular hypertrophy, and cigarette smoking.

Mechanisms Of Vascular Toxicity

Thesis and metabolism of dimethylarginines are not completely understood however, they are probably formed from the degradation of methylated proteins (58). Endothelial cells are capable of synthesizing small amounts of ADMA (59), and this synthesis is upregulated in the presence of methionine or homocysteine (60). The production of ADMA by human endothelial cells is regulated by S-adenosylmethionine-dependent methyltransferases, and production is upregulated by native or oxidized low-density lipoprotein. This provides a mechanism by which homocysteine can impair endothelial function, particularly in the presence of hypercholesterolemia. The hypothesis that ADMA is an important mediator of homocysteine-induced dysfunction is further supported by data showing that, in monkeys, diet-induced hyperhomocysteinaemia produced twofold to threefold increases in both tHcy and ADMA. However, supplementation with B-group vitamins decreased the plasma level of tHcy but did not affect the plasma...

Enterohepatic Bile Acid Transporters In Liver Disease

Mutations in the SLC10A2 gene encoding ASBT have been identified that can cause primary bile acid malabsorption, a rare disorder of the intestine characterized by congenital diarrhoea, steatorrhea and reduced plasma cholesterol levels.38 The ASBT variants carrying these mutations exhibit severely reduced bile acid transport activity in vitro.

Diabetes And Circulatory Problems

Even though people with type 1 diabetes generally do not have high blood pressure and high cholesterol problems, they can develop heart disease after many years. This is especially likely to occur if they have diabetic kidney disease. Improve your lipid profile. People with type 2 diabetes frequently have abnormalities of their lipid profile a collective term for cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol levels. Almost all people with type 2 diabetes and many with type 1 diabetes need to take medicines for the lipid abnormalities. Triglycerides are an energy source of the body made in the intestine and the liver. They consist of three fatty acid chains combined with glycerol. Cholesterol and triglycerides combine with proteins to form lipoprotein particles that circulate in the blood. These particles include the following High-density lipoproteins (HDL), which are made in the liver and intestines HDL cholesterol is known as the good cholesterol In people with...

Generalization Of Controlled Randomized Trials

In early 1970s, a high cholesterol level was known to be a risk factor for developing coronary heart disease. To confirm this, a trial known as the Lipids Research Clinics Coronary Primary Prevention Trials (CPPT) was initiated by the National Heart, Lung, and Blood Institute to test the hypothesis whether lowering cholesterol can prevent the development of coronary heart disease. In the CPPT trial, a total of 4000 healthy, middle-age males were randomized to receive either the cholesterol-lowering agent cholestyramine or its matching placebo (Lipids Research Clinics Program, 1984). The primary endpoint was the incidence of coronary heart disease after a seven-year follow-up. A statistically significant reduction of 1.7 in 7-year incidence of coronary heart diseases was observed for the cholestyramine group as compared to the placebo (8.1 versus 9.8 ). An expert panel recommended to extrapolate the results for the treatment of high cholesterol in populations that had never been...

Summary and Conclusions

Design new therapeutic agents, e.g. for treatment of cardiac failure, hypercholesterolemia, or for treatment of obesity without the central effect that most other anti-obesity drugs display. This could be a very important pharmaceutical progress in the solution of the increasing obesity epidemic in the Western world.

Do surrogate markers predict benefit in individuals

It has been generally assumed that only patients with hypercholesterolemia or hypertension benefit from lipid-lowering or antihypertensive treatment. Recent trial reports, however, have raised questions about these assumptions. The Heart Protection Study1 investigated simvastatin (Zocor) vs. placebo taken over 5 years in 20,500 subjects. The fairly unselected study population included those with normal and abnormal serum lipids, as well as those with and without a history of vascular disease. Convincing subgroup analyses demonstrated that subjects with normal lipids and no vascular history (i.e., those with no indication for statin treatment) benefited the same as those in other subgroups, in terms of relative event reduction. The authors raised the logical question -- Is elevated total or LDL cholesterol in serum a reliable indicator for initiation of lipid-lowering (statin) treatment Should treatment guidelines and treatment decisions be based only on these measures Clearly, drugs...

Definitions Of Lipids

The traditional definition of total fat of foods used by the U.S. Food and Drug Administration (FDA) has been the sum of the components with lipid characteristics that are extracted by Association of Official Analytical Chemists (AOAC) methods or by reliable and appropriate procedures.'' The FDA has changed from a solubility-based definition to total lipid fatty acids expressed as triglycerides'' 4 , with the intent to measure caloric fatty acids. Solubility and size of fatty acids affect their caloric values. This is important for products that take advantage of this, such as Benefat Salatrim, so these products would be examined on a case-by-case basis. Food products containing sucrose polyesters would require special methodology to calculate caloric fatty acids. Foods containing vinegar ( 4.5 acetic acid) present a problem because they will be considered to have 4.5 fat unless the definition is modified to exclude water-soluble fatty acids or the caloric weighting for acetic acid is...

Free Fatty Acids and Nitric Oxide

Increased levles of free FAs causes increased very LDL production and cholesteryl ester synthesis. The resulting increased triglycerides found in diabetic subjects, coupled with the lower high-density lipoprotein (HDL), have also been associated with endothe-lial dysfunction (134,135).

Peroxisome Proliferator Activated Receptora in Vascular Biology Inflammation and Atherosclerosis

The clinical trials using fibrates could be considered in some sense tests of the cardiovascular effects of PPAR-a agonists. In the Veterans Affairs HDL Intervention Trial, patients with a prior history of cardiovascular disease and a relatively average LDL, low HDL, and only modestly elevated triglycerides experienced fewer recurrent cardiac events in response to the fibrate gemfibrozil as compared to placebo (23). It remains both

Mainstream drugs from edible plants

Certain active pharmaceutical ingredients occur naturally in food plants and spices. With a few notable exceptions (statins, xanthines, capsaicinoids), the concentrations are very low and unlikely to exert any direct significant pharmacological activity. This background dietary 'pharmaceutical noise' can, however, become significant under particular conditions, especially in the realm of exposure to recreational drugs like tobacco and opioids.

The Metabolic Syndrome in HIVinfected Individuals

The metabolic syndrome may be even more common in HIV-infected individuals there are many possible reasons. HIV infection on its own may exacerbate many of the manifestations of the metabolic syndrome, particularly elevation in serum triglycerides this was seen in HIV-infected individuals prior to the advent of antiretro-viral therapy. In addition, many HIV-infected individuals smoke (50 vs. 25 in the US population overall), and many HIV-infected individuals have hypertension. The metabolic syndrome may be exacerbated by some of the drugs used to treat HIV infection, including thymidine analog reverse transcriptase inhibitors and some protease inhibitors both tend to increase triglycerides and cholesterol, and may be associated with glucose intolerance. Waist circumference in women in men Triglycerides HDL Glucose

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