Comprehensive validation of the functional assessment of anorexia/cachexia therapy (FAACT) anorexia/cachexia subscale (A/CS) in lung cancer patients with involuntary weight loss.

PURPOSE: Comprehensive (qualitative and quantitative) assessments of the 12-item functional assessment of anorexia/cachexia therapy (FAACT) anorexia/cachexia subscale (A/CS) and relevant subscales were undertaken for use in constructing potential endpoints in clinical trials of non-small cell lung cancer (NSCLC) with involuntary weight loss. METHODS: Eleven participants (≥ 18 years) from six clinical sites with a diagnosis of stage III unresectable or stage IV NSCLC and involuntary weight loss (either ≥ 5% body weight loss within six months prior to screening or screening BMI < 20 kg/m2) were interviewed to evaluate the content validity of the A/CS domain. A psychometric evaluation was conducted on the A/CS domain, and symptoms and concerns subscales, using data from previously completed phase III clinical trials (ROMANA1 [N = 474] and ROMANA2 [N = 488]). RESULTS: Anorexia-related symptoms were highly relevant to participants and had important impacts on their lives including energy levels, and physical, social, and psychological functioning. The majority of participants endorsed the A/CS domain items and found them to be easily understood, relevant, and comprehensive. Confirmatory factor analyses established that the A/CS symptoms and concerns subscales provided an acceptable fit as single factor models in ROMANA1 and ROMANA2. Reliability, validity, and responsiveness were established for the 12item A/CS domain, 5item anorexia symptoms subscale, and 4-item anorexia concerns subscale. CONCLUSIONS: These scales have good content validity, favorable psychometric properties, and can be used for characterizing the effect of treatment on anorexia symptoms and/or anorexia-related concerns in patients with NSCLC.

L-carnitine increases liver alpha-tocopherol and lowers liver and plasma triglycerides in aging ovariectomized rats.

The objective of this study was to determine whether dietary L-carnitine can influence the status of alpha-tocopherol, retinol and selected lipid parameters in aging ovariectomized rats, an animal model for the menopausal state. Fourteen Fisher-344 female rats 18 months old were acclimated for 4 weeks and ovarectomized. Seven rats per treatment were assigned to either a control group fed ad libitum AIN-93M diet or a carnitine group fed the same diet supplemented with L-carnitine. After an 8-week feeding period, blood and selected tissues were taken for analyses. No differences were noted in food intake, body weight, or organ weights due to L-carnitine. Dietary carnitine significantly increased liver alpha-tocopherol and tended to increase plasma alpha-tocopherol (P<.09). No changes in alpha-tocopherol were observed in other tissues including the brain, lungs and retroperitoneal fat. Retinol levels in plasma and tissues were not affected by supplemental L-carnitine. Significant decreases in liver and plasma triglyceride (TG) levels were noted, suggesting increased utilization of fatty acids. No differences were observed in the fatty acid profile of tissues. The results provide evidence that dietary supplementation of L-carnitine enhances the alpha-tocopherol status and improves the utilization of fat leading to lowering of the liver and plasma levels of TG in aging ovariectomized rats. Whether supplemental L-carnitine may be of benefit to postmenopausal women in lowering plasma TG and improving the antioxidant status remains to be studied.

A combination therapy including psyllium and plant sterols lowers LDL cholesterol by modifying lipoprotein metabolism in hypercholesterolemic individuals.

We conducted a randomized, double blind, crossover, placebo-controlled study to determine the effects of a combination therapy including plant sterols (PS) and psyllium (PSY), provided via cookies, on plasma lipids and on the size and subfraction distribution of VLDL, LDL, and HDL. Thirty-three healthy free-living individuals (11 males and 22 females), aged 35-65 y, with a BMI between 25 and 35 kg/m(2) and initial plasma LDL cholesterol (LDL-C) concentrations between 2.6 and 4.1 mmol/L (100 and 160 mg/dL), were randomly assigned to receive treatment cookies (7.68 g/d PSY and 2.6 g/d PS) or placebo cookies (0 g PSY+PS) for 4 wk. After a 3-wk washout period, subjects received the other cookies for an additional 4 wk. Plasma total cholesterol concentrations were significantly reduced for all subjects, from 5.65 +/- 0.72 mmol/L after the placebo period to 5.28 +/- 0.76 mmol/L after the PSY+PS cookie period (P < 0.01). These reductions were primarily in LDL-C, which decreased from 3.48 +/- 0.70 to 3.14 +/- 0.78 mmol/L after PSY+PS cookie consumption (P < 0.01). Intake of the PSY+PS cookie decreased the number of intermediate density lipoprotein (IDL), LDL, and HDL particles (P < 0.05) and plasma apo B concentrations (P < 0.01). The decreases in LDL and HDL particles were in the small subfractions. Because smaller LDL particles are associated with an increased risk of heart disease and because smaller HDL particles are indicative of diminished reverse cholesterol transport, we conclude that the combination therapy resulted in a less atherogenic lipoprotein profile. In addition, the evaluation of lipoprotein subfractions resulting from the action of the fiber and plant sterols in the intestinal lumen provides an insight on the secondary mechanisms of plasma LDL-C lowering.

Validation of using gene expression in mononuclear cells as a marker for hepatic cholesterol metabolism.

HMG-CoA reductase and the LDL receptor are ubiquitously expressed in major tissues. Since the liver plays a major role in regulating circulating LDL, it is usually of interest to measure the effects of drug or dietary interventions on these proteins in liver. In humans, peripheral blood mononuclear cells have been used as a surrogate for liver to assess regulation of these genes, although there is concern regarding the validity of this approach. The purpose of this study was to evaluate the relationship between liver and mononuclear cell expression of HMG-CoA reductase and the LDL receptor in guinea pigs, a well established model for human cholesterol and lipoprotein metabolism. We extracted RNA from liver and mononuclear cells of guinea pigs from a previous study where the effects of rapamycin, an immunosuppresant drug used for transplant patients, on lipid metabolism were evaluated. Guinea pigs were assigned to three different diets containing the same amount of fat (15 g/100 g) and cholesterol (0.08 g/100 g) for a period of 3 weeks. The only difference among diets was the concentration of rapamycin: 0, 0.0028 or 0.028 g/100 g. There were no differences in plasma LDL cholesterol (LDL-C) among groups. Values were 78.4 +/- 14.3, 65.8 +/- 17.2 and 68.4 +/- 45.4 mg/dL (P > 0.05) for guinea pigs treated with 0, low or high doses of rapamycin, respectively. The mRNA abundance for the LDL receptor and HMG-CoA reductase was measured both in liver (n = 30) and mononuclear cells (n = 22) using reverse transcriptase PCR. In agreement with the finding of no changes in plasma LDL-C, there were also no differences for the expression of HMG-CoA reductase or the LDL receptor among groups. However, a positive correlation was found between liver and mononuclear cells for both HMG-CoA reductase (r = 0.613, P < 0.01) and the LDL receptor (r = 0.622, P < 0.01). These correlations suggest that monocytes can be used in humans as an index for liver to assess diet and drug effects on the expression of HMG-CoA reductase and the LDL receptor.

Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs.

This study was designed to define some of the mechanisms by which rapamycin (RAPA), an mTOR inhibitor, induces hypertriglyceridemia when used as an immunosuppressive or antiproliferative agent and to determine whether low doses result in less undesirable side effects. Thirty male guinea pigs (n=10 per group) were randomly assigned to control (no RAPA), low-RAPA (0.08 mg/d), or high-RAPA (0.85 mg/d) treatment for 3 weeks. Rapamycin treatment resulted in more than a 2-fold increase in plasma triglycerides (TG) (P<.01), whereas no differences were observed in plasma cholesterol between RAPA and control groups. Low-RAPA treatment resulted in lower concentrations of cholesterol in the aorta (28.6%) and lower hepatic acyl-CoA cholesteryl acyltransferase activity compared to control and high-RAPA groups (P<.01). In addition, acyl-CoA cholesteryl acyltransferase activity was positively correlated with aortic cholesterol (r=0.43, P<.05). In contrast, aortic TG concentrations were higher in RAPA-treated guinea pigs than in control (P<.01). Very low density lipoprotein and low-density lipoprotein particles isolated from guinea pigs treated with RAPA were larger in size and contained more TG molecules than particles from control animals. Interestingly, plasma free fatty acids and fasting plasma glucose were 65% and 72% higher in the high-RAPA group than in control (P<.01). Tumor necrosis factor-alpha concentrations in the aorta were 3.6- and 10.4-fold higher in the low-RAPA and high-RAPA groups than in control guinea pigs (P<.01). These results suggest that RAPA interferes with TG metabolism by altering the insulin signaling pathway, inducing increased secretion of very low density lipoprotein and promoting deposition of TG in the aorta. Low RAPA was found to decrease cholesterol accumulation in tissue (liver and aorta) compared to high RAPA, suggesting that lower doses could be less detrimental to transplant patients.

Maintenance of the LDL cholesterol:HDL cholesterol ratio in an elderly population given a dietary cholesterol challenge.

We previously evaluated the responses to dietary cholesterol in children and young adults. In this study, the effects of dietary cholesterol on plasma lipids and LDL atherogenicity were evaluated in 42 elderly subjects (29 postmenopausal women and 13 men > 60 y old). Our exclusion criteria were diabetes, heart disease, and the use of reductase inhibitors. The study followed a randomized crossover design in which subjects were assigned to consume the equivalent of 3 large eggs (EGG) daily or the same amount of a cholesterol-free, fat-free egg substitute (SUB) for a 1-mo period. After a 3-wk washout period, subjects were assigned to the alternate treatment. The concentration of plasma cholesterol after the EGG period varied among subjects. When all subjects were evaluated, there were significant increases in LDL cholesterol (LDL-C) (P < 0.05) and HDL-C (P < 0.001) for both men and women during the EGG period, resulting in no alterations in the LDL-C:HDL-C or the total cholesterol:HDL-C ratios. In addition, the LDL peak diameter was increased during the EGG period for all subjects. In contrast, the measured parameters of LDL oxidation, conjugated diene formation, and LDL lag time did not differ between the EGG and the SUB periods. We conclude from this study that dietary cholesterol provided by eggs does not increase the risk for heart disease in a healthy elderly population.

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs.

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress.

To evaluate the effects of grape polyphenols on plasma lipids, inflammatory cytokines, and oxidative stress, 24 pre- and 20 postmenopausal women were randomly assigned to consume 36 g of a lyophilized grape powder (LGP) or a placebo for 4 wk. The LGP consisted of 92% carbohydrate and was rich in flavans, anthocyanins, quercetin, myricetin, kaempferol, and resveratrol. After a 3-wk washout period, subjects were assigned to the alternate treatment for an additional 4 wk. The placebo consisted of an equal ratio of fructose and dextrose and was similar in appearance and energy content (554 kJ) to LGP. Plasma triglyceride concentrations were reduced by 15 and 6% in pre- and postmenopausal women, respectively (P < 0.01) after LGP supplementation. In addition, plasma LDL cholesterol and apolipoproteins B and E were lower due to LGP treatment (P < 0.05). Further, cholesterol ester transfer protein activity was decreased by approximately 15% with intake of LGP (P < 0.05). In contrast to these beneficial effects on plasma lipids, LDL oxidation was not modified by LGP treatment. However, whole-body oxidative stress as measured by urinary F(2)-isoprostanes was significantly reduced after LGP supplementation. LGP also decreased the levels of plasma tumor necrosis factor-alpha, which plays a major role in the inflammation process. Through alterations in lipoprotein metabolism, oxidative stress, and inflammatory markers, LGP intake beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women.

High intake of saturated fat and early occurrence of specific biomarkers may explain the prevalence of chronic disease in northern Mexico.

To investigate whether the high prevalence of coronary heart disease (CHD) and type II diabetes prevalent in Northern Mexico could be related to the presence at a young age of biomarkers for chronic disease, 25 boys and 29 girls (8-12 y old) from a low socioeconomic group were recruited. Plasma lipids, LDL phenotype, apolipoproteins (apos), glucose, and insulin were evaluated. Analysis of 3-d dietary records indicated the typical intake of this region to be high in total fat (37-43% energy) and saturated fat (11-13% energy). Boys and girls had an average of 6623 +/- 2892 and 6112 +/- 2793 steps/d, respectively, as measured by a pedometer, suggesting a low level of activity. Plasma total and LDL cholesterol (LDL-C) were within the 50th percentile. In contrast, the study population was characterized by having high triglycerides (TG) (95th percentile, 1.25 +/- 0.37 mmol/L in boys and 1.19 +/- 0.38 mmol/L in girls). HDL cholesterol (HDL-C) concentrations were low (25th percentile), 1.22 +/- 0.20 mmol/L in girls and 1.29 +/- 0.20 mmol/L in boys. There was also a high prevalence of the small dense LDL phenotype B (69%), which is associated with increased risk for CHD. These results suggest that the population of children studied may have 2 different components of risk, one being the high-fat diet, which could be associated with the elevated levels of plasma LDL-C present in the adult population. A second component, related to the insulin resistance syndrome, may be principally genetic and associated with the high TG, low HDL, and LDL phenotype B observed in these Mexican children.