Serum leptin and cytokines in whole blood in relation to clinical and nutritional status in cystic fibrosis.

OBJECTIVES: Leptin plays an important role in the energy balance and may be affected by hormonal and metabolic derangement associated with chronic disease. The aim of this study was to assess the correlation between leptin, proinflammatory cytokines and nutritional status with regard to clinical status in homozygous delta F 508 cystic fibrosis patients. METHODS: Patients with mild (Shwachman score 71-100 points, group A) disease were compared with those with moderate disease (Shwachman score 41-55 points, group B) and age-matched controls (group C, n = 22). Leptin was assessed by enzyme-linked immunosorbent assay and cytokines (interleukin-8, tumor necrosis factor alpha) before and after stimulation with 5 ng lipopolysaccharide by a chemiluminescent immunometric assay. RESULTS: Twenty-two patients were recruited for each group (median A/B/C forced expiratory volume in 1 second 80%/59%/-; median age 12/13.5/12.5 years). Leptin (median 3.25/2.65/3.3 pg/mL; P = 0.083) and body mass index were lower (group A/B/C 18.55/16.75/20.5 kg/m(2); P = 0.023), but dietary intake was significantly higher (group A/B/C 50.5/68/43 kcal/kg body weight; P = 0.026) in moderate disease. Cytokines before stimulation with lipopolysaccharide were highest in moderate disease, but there was no significant difference after stimulation (interleukin-8 median A/B/C before--15/25.1/8.0 pg/mL, P < 0.005; after--570.5/573.5/415.5 pg/mL, not significant; tumor necrosis factor alpha median A/B/C 43/56/30 pg/mL, P < 0.0001; 580/427/720.5 pg/mL, not significant.). CONCLUSIONS: There is a physiological regulation of leptin even in more advanced states of disease with significantly lower body mass index than controls. However, our data do not support the idea of elevated cytokine levels inducing anorexia in homozygous delta F 508 cystic fibrosis patients.

Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin.

BACKGROUND AND OBJECTIVE: The polymorphism of SLCO1B1 (solute carrier organic anion transporter family, member 1B1), encoding the hepatic uptake transporter organic anion transporting polypeptide 1B1, has been associated with increased pravastatin concentrations in single-dose studies. We have investigated whether this polymorphism influences the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin. METHODS: A prospective, parallel-group study of 16 healthy volunteers, including 8 carriers of an SLCO1B1 variant haplotype and 8 control subjects, was carried out. Pravastatin pharmacokinetics and reduction in total and low-density lipoprotein (LDL) cholesterol concentrations were analyzed after treatment with 40 mg pravastatin daily for 3 weeks. RESULTS: The mean area under the plasma concentration-time curve of pravastatin was 110% higher (305.0 +/- 149.4 ng . h/mL [mean +/- SD] versus 144.9 +/- 48.2 ng . h/mL, P = .012) and the mean peak concentration in plasma was 231% higher (174.5 +/- 98.6 ng/mL versus 52.7 +/- 22.1 ng/mL, P = .0042) in the SLCO1B1 variant haplotype group than in the control group. Pravastatin significantly reduced the concentrations of total and LDL cholesterol in both groups. The mean percentage reduction in total cholesterol concentration was 13.1% +/- 9.1% and 19.1% +/- 8.3% in the variant and control groups, respectively (P = .19; 95% confidence interval of difference between groups, -15.3% to 3.3%). The mean percentage reduction in LDL cholesterol concentration was 27.7% +/- 8.3% in the variant group and 32.3% +/- 11.2% in the control group (P = .37; 95% confidence interval for difference, -15.1% to 6.0%). CONCLUSIONS: Despite considerably higher plasma pravastatin concentrations in carriers of an SLCO1B1 variant haplotype, there was no significant difference in the lipid-lowering efficacy of pravastatin between the variant haplotype and control groups. However, this pilot study had sufficient statistical power to detect only a large difference in lipid response between the 2 groups. Further clinical studies are warranted to characterize the impact of the SLCO1B1 polymorphism on the lipid response to pravastatin.

Lipopolysaccharide binding protein, cytokine production in whole blood, and lipoproteins in cystic fibrosis.

According to the endotoxin lipoprotein hypothesis, lipoproteins may down-regulate cytokine production by neutralizing lipopolysaccharide (LPS) binding protein (LBP) complexes. We investigated the correlation between lipoproteins, LBP, cytokine production, and clinical status in Delta F 508 (homozygous) individuals. Cystic fibrosis patients with mild disease were compared with those with more severe disease and age-matched controls. LBP, IL-8, and tumor necrosis factor-alpha, using a chemiluminescent immunometric assay, and fat intake, as well as serum triglycerides, cholesterol, very low density lipoprotein, LDL, and HDL were measured. In more severe disease there was a correlation between maximum expiratory flow at 25% of vital capacity and HDL. To adjust for the influence of colonization with Pseudomonas aeruginosa, those who were colonized with P. aeruginosa were analyzed separately. There was a significant correlation between LBP and forced expiratory volume in 1 s. Lipoproteins may have a modulating effect in more advanced disease and are not influenced by fat intake. LBP correlates those who were colonized with P. aeruginosa (Psa+) with clinical status as well as lung function and may be a critical molecule regulating LPS-induced inflammation.

[Pleiotrophic effect of statins (3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors)]. / Pleiotrophe Effekte von Statinen (3-Hydroxy-3-Methylglutaryl-Coenzym A-Reduktasehemmer).

The development of statins improved the therapy of hypercholesterolemia and atherosclerotic disease tremendously. The beneficial effects of statins were clearly demonstrated in large scale primary and secondary prevention studies. In addition to the reduction of plasma cholesterol, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase also results in the depletion of intermediates of cholesterol biosynthesis that are important for cellular integrity. The so called pleiotrophic effects of statins and probably also their adverse events can be attributed to the inhibition of synthesis of these intermediates. The review article describes the pathogenesis of atherosclerosis, the pharmacokinetic and pharmacodynamik of statins, and their pleiotrophic effects concerning endothelial function, LDL (low density lipoprotein) oxidation, macrophages, smooth muscle cell proliferation, atherosclerotic plaque, platelets, thrombosis, proinflammatory factors, haemorheology, hypertension, venous thrombosis, bone metabolism, stroke, and the possible influence on the prevention of Alzheimer's disease.

Comparison of the intestinal uptake of cholesterol, plant sterols, and stanols in mice.

The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitosterolemia suggests that intestinal uptake of cholesterol is an unselective process, and that discrimination between cholesterol and plant sterols takes place at the level of sterol efflux from the enterocyte. Although plant sterols are structurally very similar to cholesterol, differing only in their side chain length, they are absorbed from the intestine to a markedly lower extent. In order to further evaluate the process of discrimination, three different sterols (cholesterol, campesterol, sitosterol) and their corresponding 5 alpha-stanols (cholestanol, campestanol, sitostanol) were compared concerning their concentration in the proximal small intestine, in serum, and in bile after a single oral dose of deuterated compounds. The data obtained support the hypothesis that i) the uptake of sterols and stanols is an extremely rapid process, ii) discrimination probably takes place on the level of reverse transport back into the gut lumen, iii) plant stanols are taken up, but not absorbed to a measurable extent, and iv) the process of discrimination probably also exists at the level of biliary excretion. The range of structural alterations that decrease intestinal absorption and increase biliary excretion is: 1) campesterol, 2) cholestanol-sitosterol, and 3) campestanol-sitostanol.

Cholesterol metabolism in patients with chronic renal failure on hemodialysis.

Premature atherosclerosis is a major concern in patients on chronic dialysis and the identification of risk factors is important for preventive and interventional strategies. Other than the recognized atherogenic lipoprotein levels, little is known about overall cholesterol metabolism in patients on chronic hemodialysis (HD) and the best therapeutic intervention is still being debated. Therefore, we investigated intestinal cholesterol absorption, cholesterol and bile acid synthesis, and non-cholesterol plasma sterols in eight patients on dialysis and compared the results to those of 16 healthy male controls matched for body mass index and dietary cholesterol intake. Total, low-density lipoprotein (LDL) cholesterol, and triglycerides did not differ between the groups, but dialysis patients had a significantly lower high-density lipoprotein (HDL) cholesterol level (39 +/- 11 mg/dL vs. 48 +/- 10 mg/dL, p < 0.045). However, fractional cholesterol absorption, was significantly lower in dialysis patients (42.8 +/- 10.9% vs. 53.4 +/- 11%, p < 0.035), whereas plasma plant sterol concentrations and their ratios to cholesterol did not differ. Bile acid and total cholesterol synthesis were lower in dialysis patients (40% and -25%, respectively), although the differences were not significant. In contrast, lathosterol and its ratio to cholesterol in plasma was significantly lower in dialysis patients (0.176 +/- 0.084 mg/dL vs. 0.251 +/- 0.102 mg/dL, p < 0.024 and 0.733 +/- 0.353 microg/mg vs. 1.172 +/- 0.407 microg/mg, p < 0.017, respectively), indicating reduced hepatic de novo cholesterol synthesis. It is concluded that reduced HDL cholesterol and reduced bile acid synthesis contributes to atherosclerosis pathogenesis in dialysis patients, whereas intestinal cholesterol absorption and hepatic cholesterol synthesis did not seem dominant in this process at this stage of disease. Consequently, treatment with bile acid binding resins could be preferable to treatment with cholesterol absorption and synthesis inhibitors.

Inhibition of intestinal cholesterol absorption by ezetimibe in humans.

BACKGROUND: Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. METHODS AND RESULTS: The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8+/-13.8% on placebo and 22.7+/-25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; P< 0.001). Cholesterol synthesis increased by 89% from 931+/-1027 mg/d on placebo to 1763+/-1098 mg/d on ezetimibe (P<0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P<0.001). Bile acid synthesis was insignificantly increased (placebo: 264+/-209 mg/d, ezetimibe: 308+/-184 mg/d; P=0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were -20.4% and -15.1%, respectively (P<0.001 for both), whereas campesterol and sitosterol were decreased by -48% and - 41%, respectively. CONCLUSION: In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.

Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin.

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the Western world, with hypercholesterolemia as the major risk factor. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors represent the most efficient drugsfor the treatment of hypercholesterolemia. They lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liverand subsequent increased expression of low-density lipoprotein (LDL) receptors, resulting in an up-regulated catabolic rate for plasma LDL. The beneficial effect of statins on the incidence of CHD was clearly demonstrated in several large-scale clinical trials. Currently, five statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available, and two novel compounds (pitavastatin, rosuvastatin) are undergoing clinical investigation. To point out potential mechanisms leading to increased toxicity and to compare the novel statins with the established ones, this article summarizes their pharmacological data since the prevalence of adverse events can be explained at least in part by their pharmacokinetic differences.