Urinary polycyclic aromatic hydrocarbon metabolites and hyperlipidemia: NHANES 2007-2016.

BACKGROUND: The relationships between urinary polycyclic aromatic hydrocarbon (PAH) metabolites and hyperlipidemia have not been thoroughly studied. The primary goal of this research focused on investigating the linkage between PAH metabolite concentrations in urine and hyperlipidemia prevalence within US adults. METHODS: A cross-sectional analysis was conducted using data from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to assess correlations between urinary PAH metabolite levels and the risk of hyperlipidemia, while restricted cubic spline models were used to examine dose‒response relationships. Subgroup and interaction analyses were performed to further elucidate these associations. Weighted quantile sum (WQS) regression analyzed the cumulative impact of various urinary PAH metabolites on hyperlipidemia risk. RESULTS: This study included 7,030 participants. Notably, individuals in the highest quintile of urinary PAH metabolite concentrations exhibited a significantly elevated prevalence of hyperlipidemia, even after comprehensive adjustments (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Moreover, elevated levels of 1-hydroxyphenanthrene and 2-hydroxynaphthalene in the fourth quintile and 2-hydroxyfluorene in the third, fourth, and fifth quintiles demonstrated positive correlations with the prevalence of hyperlipidemia. These associations persisted across subgroup analyses. Additionally, a positive correlation between the urinary PAH metabolite mixture and hyperlipidemia (positive model: OR = 1.04, 95% CI: 1.00-1.09) was observed in the WQS model, and 2-hydroxynaphthalene showed the most substantial contribution. CONCLUSION: The cross-sectional analysis identified a significant correlation between urinary PAH metabolite and hyperlipidemia prevalence within the US demographic, with 2-hydroxynaphthalene being the predominant influencer. These findings underscore the need to mitigate PAH exposure as a preventive measure for hyperlipidemia.

The Changes in Endogenous Metabolites in Hyperlipidemic Rats Treated with Herbal Mixture Containing Lemon, Apple Cider, Garlic, Ginger, and Honey.

An herbal mixture composed of lemon, apple cider, garlic, ginger and honey as a polyphenol-rich mixture (PRM) has been reported to contain hypolipidemic activity on human subjects and hyperlipidemic rats. However, the therapeutic effects of PRM on metabolites are not clearly understood. Therefore, this study aimed to provide new information on the causal impact of PRM on the endogenous metabolites, pathways and serum biochemistry. Serum samples of hyperlipidemic rats treated with PRM were subjected to biochemistry (lipid and liver profile) and hydroxymethylglutaryl-CoA enzyme reductase (HMG-CoA reductase) analyses. In contrast, the urine samples were subjected to urine metabolomics using 1H NMR. The serum biochemistry revealed that PRM at 500 mg/kg (PRM-H) managed to lower the total cholesterol level and low-density lipoprotein (LDL-C) (p < 0.05) and reduce the HMG-CoA reductase activity. The pathway analysis from urine metabolomics reveals that PRM-H altered 17 pathways, with the TCA cycle having the highest impact (0.26). Results also showed the relationship between the serum biochemistry of LDL-C and HMG-CoA reductase and urine metabolites (trimethylamine-N-oxide, dimethylglycine, allantoin and succinate). The study's findings demonstrated the potential of PRM at 500 mg/kg as an anti-hyperlipidemic by altering the TCA cycle, inhibiting HMG-CoA reductase and lowering the LDL-C in high cholesterol rats.

Urinary metabolomics analysis of the protective effects of Daming capsule on hyperlipidemia rats using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

Hyperlipidemia is recognized as one of the most important risk factors for morbidity and mortality due to cardiovascular diseases. Daming capsule, a Chinese patent medicine, has shown definitive efficacy in patients with hyperlipidemia. In this study, serum biochemistry and histopathology assessment were used to investigate the lipid-lowering effect of Daming capsule. Furthermore, urinary metabolomics based on ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry was conducted to identify the urinary biomarkers associated with hyperlipidemia and discover the underlying mechanisms of the antihyperlipidemic action of Daming capsule. After 10 weeks of treatment, Daming capsule significantly lowered serum lipid levels and ameliorated hepatic steatosis induced by a high-fat diet. A total of 33 potential biomarkers associated with hyperlipidemia were identified, among which 26 were robustly restored to normal levels after administration of Daming capsule. Pathway analysis revealed that the lipid-lowering effect of Daming capsule is related to the regulation of multiple metabolic pathways including vitamin B and amino acid metabolism, tricarboxylic acid cycle, and pentose phosphate pathway. Notably, the study demonstrates that metabolomics is a powerful tool to elucidate the multitarget mechanism of traditional Chinese medicines, thereby promoting their research and development.

Urinary Levels of the Acrolein Conjugates of Carnosine Are Associated with Cardiovascular Disease Risk.

Carnosine is a naturally occurring dipeptide (ß-alanine-L-histidine) which supports physiological homeostasis by buffering intracellular pH, chelating metals, and conjugating with and neutralizing toxic aldehydes such as acrolein. However, it is not clear if carnosine can support cardiovascular function or modify cardiovascular disease (CVD) risk. To examine this, we measured urinary levels of nonconjugated carnosine and its acrolein conjugates (carnosine-propanal and carnosine-propanol) in participants of the Louisville Healthy Heart Study and examined associations with indices of CVD risk. We found that nonconjugated carnosine was significantly associated with hypertension (p = 0.011), heart failure (p = 0.015), those categorized with high CVD risk (p < 0.001), body mass index (BMI; p = 0.007), high sensitivity C-reactive protein (hsCRP; p = 0.026), high-density lipoprotein (HDL; p = 0.007) and certain medication uses. Levels of carnosine-propanal and carnosine-propanol demonstrated significant associations with BMI, blood glucose, HDL and diagnosis of diabetes. Carnosine-propanal was also associated with heart failure (p = 0.045) and hyperlipidemia (p = 0.002), but no associations with myocardial infarction or stroke were identified. We found that the positive associations of carnosine conjugates with diabetes and HDL remain statistically significant (p < 0.05) in an adjusted, linear regression model. These findings suggest that urinary levels of nonconjugated carnosine, carnosine-propanal and carnosine-propanol may be informative biomarkers for the assessment of CVD risk-and particularly reflective of skeletal muscle injury and carnosine depletion in diabetes.

Alteration of Angiopoietin-Like Protein 4 Levels in Serum or Urine Correlate with Different Biochemical Markers in Hyperlipidemia-Related Proteinuria.

Angiopoietin-like protein 4 (ANGPTL4) is widely known as a key regulator of lipid metabolism. We investigated the relationship between ANGPTL4 expression in serum or urine and blood lipid or urine protein levels of patients with hyperlipidemia- (HL-) related proteinuria. Sixty-eight patients with HL-related proteinuria (HL-Pro group), 68 patients with HL without proteinuria (HL-NPro group), 46 patients with non-HL-related proteinuria (NHL-Pro group), and 50 healthy control (Con) subjects were selected. There were no significant differences in serum ANGPTL4 levels between the Con group (36.82 ± 17.03 ng/ml) and the HL-Pro group (27.94 (18.90, 53.72) ng/ml). Additionally, the serum ANGPTL4 levels in the HL-Pro group were significantly lower than those in the HL-NPro group (53.32 ± 24.01 ng/ml) (P < 0.001). The urine ANGPTL4/Cr levels in the HL-Pro group (52.01 (45.25, 79.79) µg/g) were significantly higher than those in the HL-NPro group (9.96 (8.35, 12.43) ng/ml) (P < 0.05). A significant alteration in urine ANGPTL4/Cr levels was observed in the NHL-Pro group (69.41 ± 55.36 µg/g) and the Con group (10.08 ± 2.38 µg/g) as well. There was no correlation between serum and urine ANGPTL4 levels of the four groups (P > 0.05). Serum ANGPTL4 levels (HL-Pro/HL-NPro group) were positively correlated with total cholesterol (TC) and triglyceride (TG) levels in hyperlipidemia patients. However, there was no correlation between urinary ANGPTL4 levels and TC or TG (P > 0.05). Urine ANGPTL4 levels were positively correlated with 24hUPro in patients with renal impairment (HL-Pro/NHL-Pro group). To summarize, ANGPTL4 may be considered an accurate predictor of proteinuria with HL. Notably, serum or urine ANGPTL4 levels indicated the degree of proteinuria or hyperlipidemia, respectively, in HL patients.

Study on urine metabolic profiling and pathogenesis of hyperlipidemia.

BACKGROUND: As a recognized risk factor for cardiovascular disease (CVD), hyperlipidemia (HLP) has developed into a high incidence disease that seriously threatens human health. Finding a new target for effective treatment of HLP will be a powerful way to reduce the incidence of CVD. The purpose of this study was to find potential biomarkers in urine of HLP patients and analyze their metabolic pathways to study the pathogenesis of HLP. METHODS: An UPLC-Q-TOF/MS technology was used to detect the metabolites in urine of 60 HLP patients and 60 normal controls. Based on PLS-DA pattern recognition, potential biomarkers related to HLP were screened out. RESULTS: 22 potential biomarkers related to HLP were identified, which involved amino acid metabolism, fatty acid metabolism, nucleotide metabolism, steroid hormone metabolism and intestinal flora metabolism, and their possible pathogenesis was found to be related to inflammatory reaction and oxidative stress. CONCLUSION: The non-targeted metabolomic method based on UPLC-Q-TOF/MS technology can effectively identify potential biomarkers in the urine of HLP patients and explore the possible pathogenesis. Our research will lay a foundation for finding new targets for the treatment of HLP and provide a basis for clinical research on the treatment of HLP.

LC-MS based urinary metabolomics study of the intervention effect of aloe-emodin on hyperlipidemia rats.

Hyperlipidemia has been highlighted to be one of the most prominent and global chronic condition nowadays. Daming capsule (DMC), a traditional Chinese medicine (TCM) preparation, has treated hyperlipidemia on clinic in China for decades. Our recent study showed that aloe-emodin (AE) is one of the main bioactive components in DMC. Therefore, the present study aims to further investigate the lipid-lowering effect by serum biochemistry and histopathological examination, and reveal the underlying mechanisms by urinary metabolomics approach. After oral administration of AE for 6 weeks, the total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-c) levels in 50 and 100 mg/kg AE groups were both decreased significantly (P < 0.05 and P < 0.001). An ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) followed by principal components analysis (PCA), partial least squares- discriminant analysis (PLS-DA), orthogonal partial least squares-discriminant analysis (OPLS-DA), correlation analysis, heat map, and KEGG pathways was employed to identify 26 potential biomarkers. Twenty three among them were restored by AE including L-citrulline, 6-methylaminopurine, imidazoleacetic acid riboside, N-acetylhistamine, 3-methyladenine, 1-methyladenosine, dopamine, N1-methyl-4-pyridone-3-carboxamide, formylanthranilic acid, 4-pyridoxate, cAMP, salsolinol, isethionate, d-ribonic acid, 3-sulfolactic acid, vitamin C, mesaconic acid, sulfosalicylic acid, salicyluric acid, N-acetylanthranilic acid, 4,6- Dihydroxyquinoline, sebacic acid and hyocholic Acid. The related metabolic pathways include TCA cycle, the metabolism of amino acids, taurine, B vitamins, purines and pyrimidines. The results indicate that AE has a favorable therapeutic effect on HFD-induced hyperlipidemia by adjusting the metabolic disorders. Notably, urinary metabolomics combined with pattern recognition analysis provides a powerful and reliable approach into the research and development of TCM and phytochemicals.

UPLC-Q-TOF/MS-based urine and plasma metabonomics study on the ameliorative effects of aspirin eugenol ester in hyperlipidemia rats.

The main objective of this study was to investigate the ameliorative effects of aspirin eugenol ester (AEE) in hyperlipidemic rat. After five-week oral administration of AEE in high fat diet (HFD)-induced hyperlipidemic rats, the impact of AEE on plasma and urine metabonomics was investigated to explore the underlying mechanism by UPLC-Q-TOF/MS analysis. Blood lipid levels and histopathological changes of liver, stomach and duodenum were also evaluated after AEE treatment. Without obvious gastrointestinal (GI) side effects, AEE significantly relieved fatty degeneration of liver and reduced triglyceride (TG), low density lipoprotein (LDL) and total cholesterol (TCH) (P<0.01). Clear separations of metabolic profiles were observed among control, model and AEE groups by using principal component analysis (PCA) and orthogonal partial least-squares-discriminate analysis (OPLS-DA). 16 endogenous metabolites in plasma and 18 endogenous metabolites in urine involved in glycerophospholipid metabolism, fatty acid metabolism, fatty acid beta-oxidation, amino acid metabolism, TCA cycle, sphingolipid metabolism, gut microflora and pyrimidine metabolism were considered as potential biomarkers of hyperlipidemia and be regulated by AEE administration. It might be concluded that AEE was a promising drug candidate for hyperlipidemia treatment. These findings could contribute to the understanding of action mechanisms of AEE and provide evidence for further studies.

Increased urine acylcarnitines in diabetic ApoE-/- mice: Hydroxytetradecadienoylcarnitine (C14:2-OH) reflects diabetic nephropathy in a context of hyperlipidemia.

Hyperlipidemia is a risk factor for initiation and progression of diabetic nephropathy but the metabolic pathways altered in the diabetic kidney in a context of hyperlipidemia remain incompletely described. Assuming that changes in urine composition reflect the alteration of renal metabolism and function, we analyzed the urine metabolite composition of diabetic (streptozotocin-treatment) and control (non diabetic) ApoE-/- mice fed a high cholesterol diet using targeted quantitative metabolomics. Urine metabolome was also compared to the plasma metabolome of the same animals. As previously shown, urine albuminuria/urine creatinine ratio (uACR) and glomerular area and plasma lipids (cholesterol, triglycerides) were more elevated in diabetic mice compared to control. After adjustment to urine creatinine, the abundance of 52 urine metabolites was significantly different in diabetic mice compared to control. Among them was a unique metabolite, C14:2-OH (3-hydroxytetradecadienoylcarnitine) that, in diabetic mice, was positively and significantly correlated with uACR, glomerular hypertrophy, blood glucose and plasma lipids. That metabolite was not detected in plasma. C14:2-OH is a long-chain acylcarnitine reminiscent of altered fatty acid beta oxidation. Other acylcarnitines, particularly the short chains C3-OH, C3-DC, C4:1, C5-DC, C5-M-DC, C5-OH that are reminiscent of altered oxidation of branched and aromatic amino acids were also exclusively detected in urine but were only correlated with plasma lipids. Finally, the renal gene expression of several enzymes involved in fatty acid and/or amino acid oxidation was significantly reduced in diabetic mice compared to control. This included the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA (Ehhadh) that might play a central role in C14:2-OH production. This study indicate that the development of diabetes in a context of hyperlipidemia is associated with a reduced capacity of kidney to oxidize fatty acids and amino acids with the consequence of an elevation of urinary acetylcarnitines including C14:2-OH that specifically reflects diabetic nephropathy.

Urinary biomarker and treatment mechanism of Rhizoma Alismatis on hyperlipidemia.

Rhizoma Alismatis (RA), a diuretic in Asia and Europe, was found to possess anti-hyperlipidemic activity. Since the biomarkers and mechanisms of RA in the treatment of hyperlipidemia are inadequate, ultra-performance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry and multivariate data analysis were employed to investigate the urinary metabolomics of RA on hyperlipidemic rats induced by high-fat diet. The metabolic profile of RA-treated hyperlipidemic group located between control and diet-induced hyperlipidemic groups. Nineteen metabolites with significant fluctuations were identified as potential biomarkers related to the hyperlipidemia and anti-hyperlipidemia of RA using partial least-squares-discriminate analysis, heatmap analysis and correlation coefficient analysis. The fluctuations of these biomarkers represented disturbances in amino acid metabolism, purine metabolism, pyrimidine metabolism and energy metabolism. After RA treatment, these perturbed metabolites were restored to normal or nearly normal levels. RA can alleviate high-fat diet-induced dysfunctions in these metabolic pathways.

Virgin Olive Oil Enriched with Its Own Phenols or Complemented with Thyme Phenols Improves DNA Protection against Oxidation and Antioxidant Enzyme Activity in Hyperlipidemic Subjects.

The effects of virgin olive oil (VOO) enriched with its own phenolic compounds (PC) and/or thyme PC on the protection against oxidative DNA damage and antioxidant endogenous enzymatic system (AEES) were estimated in 33 hyperlipidemic subjects after the consumption of VOO, VOO enriched with its own PC (FVOO), or VOO complemented with thyme PC (FVOOT). Compared to pre-intervention, 8-hydroxy-2'-deoxyguanosine (a marker for DNA damage) decreased in the FVOO intervention and to a greater extent in the FVOOT with a parallel significant increase in olive and thyme phenolic metabolites. Superoxide dismutase (AEES enzyme) significantly increased in the FVOO intervention and to a greater extent in the FVOOT with a parallel significant increase in thyme phenolic metabolites. When all three oils were compared, FVOOT appeared to have the greatest effect in protecting against oxidative DNA damage and improving AEES. The sustained intake of a FVOOT improves DNA protection against oxidation and AEES probably due to a greater bioavailability of thyme PC in hyperlipidemic subjects.

A (1)H NMR-Based Metabonomic Investigation of Time-Related Metabolic Trajectories of the Plasma, Urine and Liver Extracts of Hyperlipidemic Hamsters.

The hamster has been previously found to be a suitable model to study the changes associated with diet-induced hyperlipidemia in humans. Traditionally, studies of hyperlipidemia utilize serum- or plasma-based biochemical assays and histopathological evaluation. However, unbiased metabonomic technologies have the potential to identify novel biomarkers of disease. Thus, to obtain a better understanding of the progression of hyperlipidemia and discover potential biomarkers, we have used a proton nuclear magnetic resonance spectroscopy ((1)H-NMR)-based metabonomics approach to study the metabolic changes occurring in the plasma, urine and liver extracts of hamsters fed a high-fat/high-cholesterol diet. Samples were collected at different time points during the progression of hyperlipidemia, and individual proton NMR spectra were visually and statistically assessed using two multivariate analyses (MVA): principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). Using the commercial software package Chenomx NMR suite, 40 endogenous metabolites in the plasma, 80 in the urine and 60 in the water-soluble fraction of liver extracts were quantified. NMR analysis of all samples showed a time-dependent transition from a physiological to a pathophysiological state during the progression of hyperlipidemia. Analysis of the identified biomarkers of hyperlipidemia suggests that significant perturbations of lipid and amino acid metabolism, as well as inflammation, oxidative stress and changes in gut microbiota metabolites, occurred following cholesterol overloading. The results of this study substantially broaden the metabonomic coverage of hyperlipidemia, enhance our understanding of the mechanism of hyperlipidemia and demonstrate the effectiveness of the NMR-based metabonomics approach to study a complex disease.

Metabolic profiling of urine in young obese men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC/Q-TOF MS).

Obesity is currently epidemic in many countries worldwide. In the young adult, obesity often accompanies hyperlipemia, which is strongly related to the occurrence and development of obesity-related chronic diseases such as diabetes mellitus, hypertension and cardiovascular disease. This study investigated the differences in metabolomic profiling between obese (with hyperlipemia, n=30) and normal-weight (n=30) young men. Anthropometric parameters and conventional metabolites were measured. There were no significant differences between obese and normal-weight young men in age, height and fasting plasma glucose level. Obese young men showed increased weight, body mass index, fat mass, systolic blood pressure, and triglyeride, total cholesterol and insulin levels, and lower levels of testosterone. The endogenous metabolite profile of urine was investigated by UPLC/Q-TOF MS (ultra performance liquid chromatography and Q-TOF mass spectrometry) with electrospray ionization (ESI). Partial least squares (PLS) enabled clusters to be visualized. Eight urine principal metabolites contributing to the clusters were identified; these included increased L-prolyl-L-proline, leucyl-phenylalanine, and decanoylcarnitine in positive ESI mode (m/z 213.1267, 279.1715 and 316.2459, respectively) and N-acetylornithine, 17-hydroxypregnenolone sulfate, 11ß-hydroxyprogesterone, 5a-dihydrotestosterone sulfate and glucosylgalactosyl hydroxylysine in negative ESI mode (m/z 173.0931, 411.1883, 331.185, 369.1751 and 485.1875, respectively). These metabolite changes in obese men suggested early changes of metabolism in young-male obesity with hyperlipemia. The study may further aid the clinical prevention and treatment of obesity and related chronic disease.

Relationship of methylglyoxal-adduct biogenesis to LDL and triglyceride levels in diabetics.

AIMS: Protein glycation leading to advanced glycation-endproducts (AGE) is enhanced in diabetes by increased blood glucose and collateral endogenous production of reactive α-dicarbonyls. Among AGE precursors, methylglyoxal (MG) is considered as one of the key intermediates. We hypothesized it to be a common product of both carbonyl and oxidative stress, and investigated its biogenesis in relation to glycemic and lipid status in diabetic patients. METHODS: Serum and urine MG-adducts were measured by competitive immunofluorometric assay in 83 diabetic and 20 healthy subjects. KEY FINDINGS: A significant association of MG-adducts serum level with LDL (r=0.31;p=0.003) was observed. A correlation between LDL-c, HDL-C and PPG as independent variables and serum MG-adducts as a dependent variable was found (p<0.014) using multiple stepwise regression, whereas urine albumin/creatinine ratio was independently associated with urine MG-adducts. LDL cut-off >3.0mmol/l discriminated patients with higher serum MG-adducts (p=0.0052), although there was no between-subgroup difference in glycemic control. Patients on statin therapy had a lower MG-adduct level. The positive relationship between LDL-c and MG-adducts (r=0.38;p=0.042) was noted in patients free of statin treatment, whereas an inverse tendency was found in the statin-treated subgroup. SIGNIFICANCE: Significant relationship between LDL and MG-adduct production, as well as tight correlation between triglycerides and urinary MG-adduct excretion suggest that the lipoxidation and glyceraldehyde-3-phosphate route, along with the glycolytic pathway, might be an important source of MG generation. The glycotoxin methylglyoxal seems to be a common factor linking hyperglycemia and intensive lipolysis, two dominant metabolic changes in diabetes.

Effects of rosuvastatin and colestimide on metabolic parameters and urinary monocyte chemoattractant protein-1 in type 2 diabetic patients with hyperlipidemia.

BACKGROUND: Rosuvastatin, a strong statin, and colestimide, a new anion exchange resin, are both clinically beneficial drugs for treatment of hypercholesterolemia. The main purpose of the study was to compare the effects of rosuvastatin and colestimide on metabolic parameters, adipokines, and markers of oxidative stress and diabetic nephropathy in patients with type 2 diabetes complicated by hyperlipidemia. DESIGN: A total of 40 patients with type 2 diabetes complicated by hyperlipidemia were recruited prospectively and consecutively. The patients were assigned randomly in equal numbers to rosuvastatin (2.5 mg/day) and colestimide (3.0 g/day) groups. Blood and urine tests were performed at the beginning of the study and after 12 weeks. RESULTS: Rosuvastatin significantly decreased the level of serum retinol-binding protein (RBP)-4, an insulin-resistant adipokine, in a subgroup of patients with poor glycemic control, in addition to exerting a strong low-density lipoprotein (LDL-C)-lowering effect. Colestimide significantly decreased HbA1c, even in patients treated with a sulfonylurea at a more than moderate dose, without influencing insulin resistance or adiponectin (an insulin-sensitive adipokine) and RBP4. Colestimide also significantly decreased the levels of urinary 8-iso-prostaglandin (PG) F2alpha (a marker of oxidative stress) and urinary monocyte chemoattractant protein-1 (MCP-1) (a marker of diabetic nephropathy). CONCLUSION: Our results show that rosuvastatin and colestimide exert different beneficial effects in type 2 diabetic patients complicated by hyperlipidemia. Therefore, concomitant use of these drugs may be useful for prevention of progression of diabetic complications.

Time-of-intake (morning versus evening) of extended-release fluvastatin in hyperlipemic patients is without influence on the pharmacodynamics (mevalonic acid excretion) and pharmacokinetics.

OBJECTIVE: Statins inhibit the rate-limiting step in cholesterol biosynthesis, the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase. Statins are usually taken in the evening as the HMG-CoA reductase activity is high during the night. This recommendation might not apply if statins are given as extended-release (ER) formulations. The present study investigated the influence of time of intake of fluvastatin 80 mg ER on cholesterol biosynthesis. Main objectives were to measure the change in 24-hour urinary mevalonic acid excretion, to determine plasma concentrations of mevalonic acid and fluvastatin and to monitor triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. METHODS: This was a randomized, 2-period crossover study in 26 hypercholesterolemic patients who received a single daily dose of fluvastatin both in the morning and in the evening. RESULTS: At baseline, the amount of mevalonic acid was 204.9 +/- 68.1 microg/g creatinine. After a single dose of fluvastatin mean urine values of mevalonate were significantly reduced to 129.8 +/- 66.2 micro/g (evening) and to 118.7 +/-34.3 microg/g (morning; n.s. between groups), thus representing a reduction of about 39%. Compared to baseline, plasma mevalonate concentrations were decreased by fluvastatin resulting in similar 24-hour profiles after the morning and the evening dosage. The pharmacokinetics of fluvastatin were similar in both periods of the study, with higher plasma concentrations for several hours following the evening dosage. CONCLUSION: This study demonstrates that fluvastatin ER is equally effective in inhibiting cholesterol biosynthesis when given once daily in the morning and once daily in the evening.

Pyridoxamine traps intermediates in lipid peroxidation reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of diabetic complications.

Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases.

Effect of high vegetable protein diets on urinary calcium loss in middle-aged men and women.

OBJECTIVE: To determine the effect of high-protein diets, which have recently been promoted for their health benefits, on urinary calcium losses and bone turnover in older subjects. DESIGN: Randomized controlled cross-over study. SETTING: Teaching hospital and university. SUBJECTS: Twenty hyperlipidemic men and postmenopausal women (age 56+/-2 y) completed the study. INTERVENTION: One-month test and control phases during which subjects consumed equi-energy metabolic diets high in calcium (1578 and 1593 mg/day, respectively). On the test diet 11% of total dietary energy from starch in the control bread was replaced by protein (wheat gluten), resulting in 27% of energy from protein on the test diet vs 16% on the control diet. MAIN OUTCOME MEASURE: Urinary calcium excretion. RESULTS: Compared with the control diet, at week 4, the test diet increased mean (+/-s.e.m.) 24 h urinary output of calcium (139+/-15 vs 227+/-21 mg, P=0.004). The treatment difference in urinary calcium loss correlated with the serum anion gap as a marker of metabolic acid production (r=0.57, P=0.011). Serum calcium levels were marginally lower 2.41+/-0.02 vs 2.38+/-0.02 mmol/l (P=0.075), but there was no significant treatment difference in calcium balance, possibly related to the high background calcium intake on both diets. CONCLUSION: In the presence of high dietary calcium intakes the vegetable protein gluten does not appear to have a negative effect on calcium balance despite increased urinary calcium loss.

Fluvastatin increases LDL particle size and reduces oxidative stress in patients with hyperlipidemia.

The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2alpha (iPF2alphaIII), a marker of oxidative stress, and low-density lipoprotein (LDL) particle size in serum were investigated in patients with hypercholesterolemia. After 6 months of fluvastatin therapy, levels of urinary iPF2alphaIII decreased from 1720.1 +/- 392.0 to 539.6 +/- 75.5 pg/mg (p < 0.01), and LDL particle size increased from 24.3 +/- 0.3 to 26.5 +/- 0.2 nm (p < 0.001). These changes from the treatment of fluvastatin were not correlated with those of the serum LDL cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique antioxidant property among statins, reduces oxidative stress and increases LDL particle size simultaneously in hyperlipidemic patients.

S-8921 (Shionogi).

S-8921 is a sodium/bile acid transport inhibitor under development by Shionogi for the potential treatment of hyperlipidemia. As of June 2000, phase I trials had commenced in Japan and were planned in Europe [370602]. S-8921 acts by altering sodium-dependent transport mechanisms of the brush-borders in the intestinal mucosa, causing bile acids that re-enter the intestine to be excreted rather than reabsorbed [281476].