Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine

BACKGROUND: We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. OBJECTIVE: The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. DESIGN: By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by > or = 1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [3H]cyclosporine translocation in Caco-2 cells were then compared. RESULTS: The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P < or = 0.007), but not with furanocoumarin-free GFJ (P > or = 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) x 10(-3) h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL(-1), respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7-8 h, respectively; P > or = 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [3H]cyclosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. CONCLUSIONS: Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein.     

Food-drug interaction: grapefruit juice augments drug bioavailability--mechanism, extent and relevance

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.     

Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice

The flavanones naringenin and hesperetin exhibit estrogenic, anticarcinogenic and antioxidative properties. Orange juice and grapefruit juice contain high amounts of these compounds, and therefore their intake from the diet can be relatively high. No data are available regarding plasma concentrations or plasma kinetics of flavanones. The objectives of this study were to develop methods allowing the analysis of naringenin and hesperetin from plasma and urine and to study their plasma kinetics and urinary excretion. We also wanted to assess whether plasma or urine flavanone concentrations can be used as biomarkers of intake. Healthy volunteers ingested orange juice (five women and three men) or grapefruit juice (two women and three men) once (8 mL/kg). Eleven blood samples and urine were collected between 0 and 24 h after juice administration. Flavanones were analyzed by HPLC with electrochemical detection. Naringenin and hesperetin were bioavailable from the studied juices, but interindividual variation in bioavailability was remarkable. The resulting plasma concentrations were comparatively high, and the peak plasma concentrations (C(max)) were 0.6 +/- 0.4 micromol/L (means +/- SD) for naringenin from orange juice and 6.0 +/- 5.4 micromol/L for naringenin from grapefruit juice. The corresponding value for hesperetin from orange juice was 2.2 +/- 1.6 micromol/L. The elimination half-lives were between 1.3 and 2.2 h, and therefore plasma concentrations reflect short-term intake. The relative urinary excretion varied depending on the flavanone source and dose and was 30.2 +/- 25.5% and 1.1 +/- 0.8% for naringenin from grapefruit juice and orange juice, respectively, and 5.3 +/- 3.1% for hesperetin from orange juice. The considerable difference in the relative urinary excretion of naringenin from the two juices was most likely caused by dose-dependent renal clearance rather than differences in bioavailability (as indicated by the similar C(max)-to-dose ratios). The results indicate that urine flavanone concentrations are not good biomarkers of dietary intake. We conclude that because of the relatively high concentrations of flavanones in plasma after ingestion of orange juice or grapefruit juice, considerable health effects could ensue in individuals consuming them regularly.     

Viable but nonculturable state of foodborne pathogens in grapefruit juice: a study of laboratory

Several foodborne human pathogens, when exposed to harsh conditions, enter viable but nonculturable (VBNC) state; however, still open is the question whether VBNC pathogens could be a risk for public health, because, potentially, they can resuscitate. Moreover, cultural methods for food safety control were not able to detect VBNC forms of foodborne bacteria. Particularly, it has not been established whether food chemophysical characteristics can induce VBNC state in contaminating pathogen bacterial populations, especially in food, such as salads and fresh fruit juices, not subjected to any decontamination treatment. In this preliminary study, we intentionally contaminated grapefruit juice to determine whether pathogen bacteria could enter VNBC state. In fact, grapefruit juice contains natural antimicrobial compounds, has an average pH of about 3 and low content in carbohydrates. Such characteristics make grapefruit juice a harsh environment for microbial survival. For this purpose, Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium ATCC 14028, Listeria monocytogenes ATCC 7644, and Shigella flexneri ATCC 12022, at two different inoculum sizes, have been used. Viability by the LIVE/DEAD BacLight Bacterial Viability kit and culturability by plate counts assay were monitored, whereas "resuscitation" of nonculturable populations was attempted by inoculation in nutrient-rich media. The data showed that L. monocytogenes lost both culturability and viability and did not resuscitate within 24?h independently on inoculum size, whereas E. coli O157:H7 was able to resuscitate after 24?h but did not after 48?h. Salmonella Typhimurium and S. flexneri, depending on inoculum size, lost culturability but maintained viability and were able to resuscitate; moreover, S. flexneri was still able to form colonies after 48?h at high inoculum size. In conclusion, entry into VBNC state differs on the species, depending, in turn, on inoculum size and time of incubation.     

Development of a comprehensive analytical method for furanocoumarins in grapefruit and their metabolites in plasma and urine using UPLC-MS/MS: a preliminary study

To develop a comprehensive analytical method for photoactive furanocoumarins, grapefruit (whole, flesh, peel and juice) was extracted using QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method. Seven furanocoumarins: bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6′,7′-dihydroxybergamottin (6′,7′-DHB), epoxybergamottin and bergamottin were determined in grapefruit using UPLC-MS/MS. The concentrations of furanocoumarins in the plasma and urine of six healthy young adults before and after ingestion of grapefruit or grapefruit juice were also determined. Recovery rates of furanocoumarins by QuEChERS method from matrix spike sample and laboratory calibrate sample were 125.7?±?25.4% and 105.7?±?6.3%, respectively. Bergamottin and 6′,7′-DHB were predominant compounds in grapefruit flesh, juice and plasma, while bergaptol and 6′,7′-DHB were major compounds detected in the urine. The results demonstrated that bergamottin and 6′,7′-DHB were metabolized to bergaptol. Overall, the analytical methods developed in the present study can be applied to the analysis of various furanocoumarins in plant sources and biological samples.     

Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer's disease

Apolipoprotein E epsilon4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion (I)/deletion (D) polymorphism (indel) of the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age, ethnic group, and carrier status of the apolipoprotein E epsilon4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction warrants further investigation.     

A longitudinal study of children's juice intake and growth: the juice controversy revisited

OBJECTIVES: To determine associations between children's longitudinal juice intake and growth parameters at age 72 months and to determine children's beverage intake patterns over time. SUBJECTS/SETTING: White children (n = 72) residing in the vicinity of a Southern US city participated in a longitudinal study. METHODS: Seven in-home interviews were conducted per child when each child was between 24 and 72 months of age. The 7 sets of 3-day dietary data were analyzed for beverage intake, categorized as juice (100% juice only), milk, carbonated beverages, and other drinks (e.g., lemonade, tea, juice drinks). The following growth parameters were determined for each child at age 72 months: height, weight, body mass index (measured as kg/m2), and ponderal index (measured as kg/m3); the 3 latter are measures of overweight. STATISTICAL ANALYSES: Associations between longitudinal juice intake and each growth parameter were tested with general linear models. Repeated measures analysis of variance tested changes in beverage intakes over time. RESULTS: There were no statistically significant associations between juice and children's height, weight, or body mass index, as tested by general linear models. Children's longitudinal juice intake was negatively related to ponderal index (beta = 0.065, P = .050). Children's juice intake decreased significantly between ages 2 and 6 years, from 6.8 to 3.6 oz/day (P = .0001); intakes of carbonated beverages and other drinks increased from 1.7 to 3.8 oz/day (P = .0016) and from 2.7 to 6.2 oz/day (P = .0001), respectively. APPLICATIONS/CONCLUSIONS: Children's longitudinal juice intake was not associated with either short stature or overweight. As juice consumption decreased, intakes of less nutritious beverages increased. Consumption of 100% juices should be encouraged by health professionals and parents/caregivers.     

Reproductive decisions as mediators between education and employment of women in Kyrgyzstan

Researchers created a large body of evidence showing that education and fertility are strong determinants of women’s employment. In postsocialist economies, women’s reproductive decisions have become more critical to employment opportunities. Yet the issue is not well-understood. The researchers focus on the mediating roles of reproductive decisions on the relationship between education and employment among Kyrgyzstani women. The study data come from the 2012 Demographic and Health Survey (N?=?2419). Consistent with other research, more education was associated with fewer number of children and being employed. An unexpected finding was that having more children was associated with increased employment.     

Liver enzymes as mediators of association between obesity and diabetes: the Guangzhou Biobank Cohort Study

PurposeTo assess the proportion of the association between obesity and diabetes mediated by liver enzymes such as gamma-glutamyltransferase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST).MethodsMediation analysis was used with adjustment for age, education, physical activity, smoking, and alcohol use.ResultsA total of 9748 participants from Phase III of the Guangzhou Biobank Cohort Study were recruited in 2006–2008. For women, the association of body mass index (BMI) and waist circumference (WC) with glucose was partially mediated by GGT, 30% (95% confidence interval 23%–40%) and 28% (23%–34%) and by ALT, 15% (14%–25%) and 14% (10%–18%), respectively; for men, the proportion mediated by GGT was 16% (9%–26%) and 23% (12%–36%), respectively, and by ALT 12% (4%–22%) for BMI and for WC. The association of BMI and WC with glucose was not mediated by AST for women or men. Additionally, considering of mediation by lipids did not change the mediation by GGT and ALT.ConclusionsThe effect of obesity on diabetes is partly mediated by GGT and ALT but not AST. There is no evidence of the mediation effect by lipids. Our results may provide opportunities to identify new targets for diabetes interventions.     

Stress and health behaviors as potential mediators of the relationship between neighborhood quality and allostatic load

Purpose

Neighborhood quality is associated with health. Increasingly, researchers are focusing on the mechanisms underlying that association, including the role of stress, risky health behaviors, and subclinical measures such as allostatic load (AL).

Use of the refractometer as a tool to monitor dietary formula concentration in gastric juice

BACKGROUND AND AIMS: Critically ill patients do not always tolerate nasogastric tube feeding. Gastric residual volumes are widely used to evaluate feeding tolerance, but controversy exists about what constitutes the residual volume (diet formula or digestive juice). In this paper, we describe the use of the refractometer as a tool to monitor dietary formula concentration in gastric juice and evaluate gastric juice refractometry as a possible clinical application. METHODS: Brix value (an index of the total solutes in solution) readings for polymeric diet at pH 1, 4, 7 and 8, and at 4 degrees C, 25 degrees C and 37 degrees C, and in fasting gastric juice were determined with a refractometer. RESULTS: We found that distilled water, minerals, and vitamins had low Brix values of 0+/-0, 1.2+/-0.1, and 0.4+/-0.1, respectively. On the other hand, because carbohydrate (17 g/100 ml), protein (5.3 g/100 ml), fat (4.1 g/100 ml), and full-strength polymeric diet had high concentrations of dissolved nutrients, they also had high Brix values (12.1+/-0.6, 6.5+/-0.1, 6.0+/-0.1, and 23.5+/-0.1, respectively). The Brix values of polymeric diet had a linear additive relationship with the diet formula concentration at various pHs, temperatures, and in the gastric juice. CONCLUSION: Brix value measurement can be used to monitor stomach dietary formula concentration. Such information can be obtained at the bedside and used to evaluate feeding-intolerant patients receiving enteral feeding.     

Cecal parameters of rats fed diets containing grapefruit polyphenols and inulin as single supplements or in a combination

OBJECTIVE: We compared the effects of grapefruit flavonoids and inulin, as single dietary components or in a combination, on cecal fermentation in rats adapted to a semipurified diet. METHODS: The experimental diets contained 0.3% flavonoid extract and 5% or 10% inulin and a combination of both supplements. The large bowel metabolism assessment was based on cecal parameters: bulk effect, pH, microbial enzymes activity, and short-chain fatty acid production. RESULTS: Both supplements induced significant enlargement of the cecal digesta weight. Acidification of cecal digesta was more pronounced, with a higher inulin addition to the diet. Cecal pH was the highest with the flavonoid-rich diets and lowest in the case of a simultaneous addition of flavonoids and a high content of inulin. The flavonoid extract applied as a single dietary supplement was observed to decrease the activity of bacterial beta-glucosidase and beta- and alpha-galactosidases in the cecal digesta. In contrast, addition of the grapefruit extract to inulin-containing diets increased the activity of alpha-glucosidase, alpha-galactosidase, and beta-galactosidase. Great accumulation of cecal digesta in rats consuming the flavonoid-diet caused a considerable increase in the short-chain fatty acid pool, mainly acetic acid. Inulin added to the diet decreased the excessive enlargement of digesta caused by dietary flavonoids. Dietary addition of inulin to the flavonoid-diet also normalized hydration of cecal digesta and significantly decreased the pH of digesta. The presence of polyphenols in the inulin-containing diets did not change total short-chain fatty acid production in the cecum of rats. CONCLUSION: Our results suggested that simultaneous intake of inulin and polyphenols can decrease the detrimental effects of the latter on cecal fermentation.     

Intake of purple grape juice as a hepatoprotective agent in Wistar rats

Grape juice is a source of polyphenols, as catechin, anthocyanidins, resveratrol, and others. Some health benefits have been attributed to these compounds (e.g., antioxidant and antitumorigenic properties). In this study, we investigated the possible antioxidant activity of two different grape juices: organic purple grape juice and conventional purple grape juice. The antioxidant activity of both grape juices was evaluated by an animal model of three groups: control and organic and conventional juices. After 30 days, all animals were sacrificed, and blood and liver were collected to evaluate lipid peroxidation level (thiobarbituric acid-reactive substances [TBARS] assay), protein oxidative level (carbonyl assay), and catalase (CAT) and superoxide dismutase (SOD) activities. The group treated with organic grape juice showed the highest SOD and CAT activities in both plasma and liver when compared with the conventional and control groups (P < .05). In plasma, we observed a positive correlation among SOD and CAT activities, resveratrol, and all anthocyanin contents, suggesting that these polyphenols may be, at least in part, responsible for this increased antioxidant defense. The grape juices were capable of reducing carbonyl and lipid peroxidation levels in plasma and liver. However, in plasma, the organic group showed lower carbonyl and TBARS levels when compared to the conventional grape juice group (P < .05). Our findings suggest that the intake of purple grape juice, especially of organic juice, induces a better antioxidant capacity when compared to conventional juice and that this may be an important issue for further investigations in the area of biochemical functional foods.