Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: a randomized cross-over study in humans.

SCOPE: Flavan-3-ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of (-)-epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross-over study in humans. METHODS AND RESULTS: Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC-MS and GC-MS/MS. Glucuronidated, sulfated, and methylated (-)-epicatechin and 5-(3',4'-dihydroxyphenyl)-valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid and their conjugated metabolites were detected. The formation of 5-(3',4'-dihydroxyphenyl)-valerolactone and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid varied largely between individuals as well as with the degree of polymerization of flavan-3-ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan-3-ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces. CONCLUSION: In addition to conjugated metabolites derived from the absorption of monomeric flavan-3-ols, 5-(3',4'-dihydroxyphenyl)-valerolactone represents an important in vivo metabolite of (-)-epicatechin and procyanidin B1 produced by the gut microbiota.

Milk whey protein modification by coffee-specific phenolics: effect on structural and functional properties.

A suitable vehicle for integration of bioactive plant constituents is proposed. It involves modification of proteins using phenolics and applying these for protection of labile constituents. It dissects the noncovalent and covalent interactions of ß-lactoglobulin with coffee-specific phenolics. Alkaline and polyphenol oxidase modulated covalent reactions were compared. Tryptic digestion combined with MALDI-TOF-MS provided tentative allocation of the modification type and site in the protein, and an in silico modeling of modified ß-lactoglobulin is proposed. The modification delivers proteins with enhanced antioxidative properties. Changed structural properties and differences in solubility, surface hydrophobicity, and emulsification were observed. The polyphenol oxidase modulated reaction provides a modified ß-lactoglobulin with a high antioxidative power, is thermally more stable, requires less energy to unfold, and, when emulsified with lutein esters, exhibits their higher stability against UV light. Thus, adaptation of this modification provides an innovative approach for functionalizing proteins and their uses in the food industry.

Effect of vitamin D3 treatment on bone density in neurofibromatosis 1 patients: a retrospective clinical study.

OBJECTIVES: We have previously demonstrated reduced bone density and an increased incidence of 25-hydroxy vitamin D3 (25-OH D3) deficiency in adults with neurofibromatosis 1 (NF1) compared to healthy controls. Vitamin D3 is a cheap, safe, and effective supplement in the general population, but its value in NF1 patients has not been demonstrated. This study investigates the therapeutic potential of oral vitamin D3 on bone mineral density (BMD) in NF1 patients with vitamin D3 deficiency. METHODS: We measured serum 25-OH D3, parathyroid hormone, calcium, and bone alkaline phosphatase concentrations, urinary deoxypyridinoline concentrations, and BMD in 35 adults with NF1. Nineteen patients received vitamin D3 supplementation for 2 years, six patients received supplementation for 1 year and 10 patients received no supplementation. Supplementation was administered in a dose that maintained the serum 25-OH D3 level above 30 µg/l. BMD was measured again at 1 and 2 years, and biochemical assessments of bone metabolism were measured at least every half year during therapy. RESULTS: Treated subjects had significantly reduced loss of BMD, as measured by T score at the hip (p=0.011) and lumbar spine (p=0.022). The effect on hip BMD was apparent at 1 year in comparison to baseline (p=0.02) and was greater at 2 years in comparison to measurements at 1 year (p=0.02). CONCLUSIONS: Vitamin D3 supplementation improves BMD in adult NF1 patients. Further studies are needed to elucidate the mechanisms responsible for reduced BMD in NF1 patients.

Characterization and modeling of the interactions between coffee storage proteins and phenolic compounds.

This study addresses the interactions of coffee storage proteins with coffee-specific phenolic compounds. Protein profiles of Coffea arabica and Coffea canephora (var. robusta) were compared. Major phenolic compounds were extracted and analyzed with appropriate methods. The polyphenol-protein interactions during protein extraction have been addressed by different analytical setups [reversed-phase high-performance liquid chromatography (RP-HPLC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and Trolox equivalent antioxidant capacity (TEAC) assays], with focus directed toward identification of covalent adduct formation. The results indicate that C. arabica proteins are more susceptible to these interactions and the polyphenol oxidase activity seems to be a crucial factor for the formation of these addition products. A tentative allocation of the modification type and site in the protein has been attempted. Thus, the first available in silico modeling of modified coffee proteins is reported. The extent of these modifications may contribute to the structure and function of "coffee melanoidins" and are discussed in the context of coffee flavor formation.

Effects of fusarium infection on the phenolics in emmer and naked barley.

Inoculated or non-inoculated naked barley and emmer cultivars were investigated with regard to their influence on phenolic acid profiles and their arabinoxylan content. Two groups of phenolic compounds were differentiated-methanol-soluble and hydrolyzable covalent-bound phenolic compounds. Chromatographic methods were applied for their analysis. The results showed ferulic acid as the predominant phenol in both total and covalent-bound fractions. The inoculation significantly reduced the ferulic acid content within a range of 5.6-6.6% in the two cereals and all their cultivars. Naked barley cultivars additionally contained the flavonoid catechin in the soluble fraction. The innoculation led here to a significant increase in the catechin content of about 4.5%. These results document an induction of the synthesis of catechin in naked barley after artificial Fusarium infection, whereas the ferulic acid content declined.

The impact of fewer hip fractures with risedronate versus alendronate in the first year of treatment: modeled German cost-effectiveness analysis.

BACKGROUND: The Risedronate and Alendronate (REAL) cohort study provides unique comparative effectiveness data for real world bisphosphonate treatment of osteoporosis. OBJECTIVE: The objective of this analysis was to assess the cost-effectiveness of risedronate compared to generic alendronate in Germany applying the REAL effectiveness data. MATERIALS AND METHODS: A validated Markov model of osteoporosis was populated with REAL effectiveness data and German epidemiological, cost, and utility data. To estimate the impact of therapy on hip fractures, costs, and quality adjusted life years (QALYs), the analysis included women>or=65 years, treated with risedronate or alendronate and followed for 4 additional years. Country-specific data included population mortality, fracture costs, and annual drug costs, using a German social insurance perspective. Costs and outcomes were discounted at 3%. A differential hip fracture relative risk reduction of 43% was applied to risedronate vs. alendronate. RESULTS: The model predicted that treatment with risedronate would result in fewer hip fractures and more QALYs at a reduced cost (savings of euro278 per treated woman) compared to treatment with generic alendronate. Sensitivity analysis assuming 2 years of treatment and equivalence of effect after 1 year show cost savings as well (euro106 per treated woman). DISCUSSION: Whereas previous economic evaluations involving bisphosphonates have mainly relied on efficacy data from noncomparative clinical trials, this study's strength is in the use of comparative effectiveness data from one data source. The magnitude of the cost savings observed were sensitive to alternative assumptions regarding treatment duration, therapy discontinuation and cost of generic alendronate. CONCLUSIONS: Based on "real world" data the analysis supports the first line use of risedronate for the treatment of osteoporotic women in Germany.

Effect of dietary genistein on Phase II and antioxidant enzymes in rat liver.

Isoflavones are thought to be biologically active components in soy that play a role in the prevention of chronic diseases including cancer. How isoflavones may mediate their beneficial effects has not yet been fully established. Potential mechanisms of cellular action of isoflavones may include their ability to modulate gene expression and the activity levels of enzymes involved in antioxidant defence and the metabolism of xenobiotics including NAD(P)H (Nicotinamide-adenine-dinucleotide-phosphate) quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST). Although there is increasing evidence from cell culture studies that genistein, the major isoflavone present in soy, may regulate the expression of genes encoding for phase II and antioxidant enzymes, little is known about its effect in vivo. Feeding rats over 3 weeks with semisynthetic diets enriched with genistein (2 g/kg) significantly increased both the hepatic mRNA and activity levels of NQO1. The total GST activity did not change in response to dietary genistein supplementation, whereas the mRNA levels of individual GST isoenzymes were differentially modulated. The hepatic mRNA level of Gsta2 (class alpha 2) was significantly increased whereas the mRNA levels of Gstm2 (class mu 2) and Gstp1 (class pi 1) were significantly lowered due to genistein supplementation. The protein level of Nrf2 (Nuclear factor E2-related factor 2), a transcription factor involved in the regulation of phase II enzymes, was not altered by dietary genistein. Furthermore, genistein did not affect the hepatic enzyme activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) or liver lipid peroxidation and glutathione levels. The induction of NQO1 may be one mechanism by which dietary genistein improves the capacity of the liver to detoxify carcinogens.

Value of a new fixed-combination pack of bisphosphonate, calcium and vitamin D in the therapy of osteoporosis: results of two quantitative patient research studies.

BACKGROUND: Osteoporotic patients with insufficient calcium intake and/or vitamin D insufficiency need adequate calcium and vitamin D supplementation with their bisphosphonate treatment. However, consistent intake and, therefore, the effectiveness of calcium/vitamin D supplementation may be impaired by several factors in the individual patient: low prescription rate or lack of advice to purchase calcium/vitamin D; reduced compliance because of the complexity of the regimen; or incorrect intake. There is a need to provide patients with a better way of taking bisphosphonate treatment with their calcium/vitamin D supplementation. To this end, a fixed-combination pack to help patients take the combination of bisphosphonate, calcium and vitamin D correctly and regularly has been developed. OBJECTIVE: To evaluate patients' understanding of administration instructions, preferences and their perceptions of compliance, convenience and completeness of a fixed-combination pack of bisphosphonate, calcium and vitamin D compared with those associated with separate packs. METHODS: The new monthly fixed-combination pack of bisphosphonate, calcium and vitamin D contains four weekly boxes. Each box contains a blister pack with one swallowable risedronate 35 mg film-coated tablet and six sachets of calcium/vitamin D effervescent granules (calcium 1000 mg and vitamin D(3) [colecalciferol] 880 IU) for dissolution in water as an oral solution, together constituting 1 week of therapy, accompanied by a patient information leaflet. Two quantitative patient research survey studies were conducted using standard questionnaires in face-to-face interviews with 400 postmenopausal women in several French cities. Participants were given the combined pack and two separate packs (risedronate 35 mg once weekly and calcium/vitamin D effervescent granules in sachets). In the first study, participants' understanding of administration instructions and preferences were evaluated. In the second study, participants' perception of compliance, convenience and completeness of the new combination pack of risedronate 35 mg plus calcium/vitamin D compared with two separate packs were evaluated. RESULTS: Participants asked about the combined pack answered a significantly higher proportion of questions about intake instructions correctly (80.3%) than participants asked about the two separate packs (70.7%) [p = 0.0004]. The combined pack was preferred by 72% of participants (p < 0.0001) for several reasons. Compared with separate packs, the combined pack was considered easier to use by 63% and easier to remember to use by 67% of participants. Participants believed that use of the combined pack would be more likely to help them take their bisphosphonate regularly (66%) and correctly (67%), and to take their calcium/vitamin D supplementation more regularly and correctly (68%), than use of separate packs. Seventy percent of participants believed that use of the combination pack would help them to not forget to take calcium/vitamin D supplementation. CONCLUSION: Use of the fixed-combination pack of risedronate 35 mg plus calcium/vitamin D once weekly could increase the likelihood that postmenopausal osteoporotic patients will receive a complete bisphosphonate, calcium and vitamin D therapy course and is likely to enhance correct intake of combination therapy. Use of this fixed-combination product will provide patients with a tool for improving adherence to recommended osteoporosis therapy and optimize the effectiveness of such treatment.

European women's preference for osteoporosis treatment: influence of clinical effectiveness and dosing frequency.

OBJECTIVE: To determine participant preference for weekly versus monthly bisphosphonate therapy for osteoporosis after being informed about differences in fracture efficacy. DESIGN: 20-minute, semi-structured, face-to-face or telephone interviews. Two bisphosphonate choices were presented on the basis of block randomization: weekly therapy with proven efficacy to reduce fracture risk at the spine and hip, or monthly therapy with proven efficacy to reduce fracture risk at the spine but not the hip. SUBJECTS: Women from the UK, Germany, France, Spain and Italy, with postmenopausal osteoporosis and aged > or = 55 years. Fifty percent were currently taking a weekly bisphosphonate; 50% had no history of taking any bisphosphonate. MEASURES: An efficacy rating scale and an intention-to-use rating scale were developed for this study. The primary endpoint was preference for weekly or monthly therapy. Reasons for preference were recorded. RESULTS: A preference was recorded for 1248 women (1253 were recruited). More women preferred weekly to monthly therapy (82% vs. 18%, respectively; p < 0.001). Among women who preferred weekly therapy, efficacy was the most commonly cited reason (65%). Ninety-two percent of the total cohort rated the efficacy of the weekly therapy as 'excellent/good' versus 38% for monthly (p < 0.001). Sixty-nine percent intended to use weekly bisphosphonates compared with 34% for monthly (p < 0.001). CONCLUSIONS: When informed about differences in fracture efficacy in weekly and monthly bisphosphonates, a significantly greater proportion (82%) of women preferred a weekly bisphosphonate with proven fracture efficacy at the spine and hip over a monthly bisphosphonate with proven fracture efficacy only at the spine.