Hesperidin Displays Relevant Role in the Nutrigenomic Effect of Orange Juice on Blood Leukocytes in Human Volunteers: A Randomized Controlled Cross-Over Study

We previously showed, in healthy, middle-aged, moderately overweight men, that orange juice decreases diastolic blood pressure and significantly improves postprandial microvascular endothelial reactivity and that hesperidin could be causally linked to the observed beneficial effect of orange juice. The objective was to determine the effect of chronic consumption of orange juice on the gene expression profile of leukocytes in healthy volunteers and to assess to what extent hesperidin is involved in the effect of orange juice.Volunteers were included in a randomized, controlled, crossover study. Throughout three 4-week periods, volunteers consumed daily: 500 ml orange juice, 500 ml control drink plus hesperidin or 500 ml control drink and placebo. Blood samplings were performed on 10 overnight-fasted subjects after the 4-week treatment period. Global gene expression profiles were determined using human whole genome cDNA microarrays. Both orange juice and hesperidin consumption significantly affected leukocyte gene expression. Orange juice consumption induced changes in expression of, 3,422 genes, while hesperidin intake modulated the expression of 1,819 genes. Between the orange juice and hesperidin consumption groups, 1,582 regulated genes were in common. Many of these genes are implicated in chemotaxis, adhesion, infiltration and lipid transport, which is suggestive of lower recruitment and infiltration of circulating cells to vascular wall and lower lipid accumulation.This study shows that regular consumption of orange juice for 4 weeks alters leukocyte gene expression to an anti-inflammatory and anti-atherogenic profile, and hesperidin displays a relevant role in the genomic effect of this beverage.ClinicalTrials.gov NCT 00983086

Prevention of post-mastectomy neuropathic pain with memantine: study protocol for a randomized controlled trial

International audienceBackground: N-methyl-D-aspartate receptor antagonists are potential therapies for neuropathic pain, and memantine has a good tolerance profile. A preclinical study recently reported that presurgery memantine may prevent neuropathic pain development and cognition dysfunction. Considering the high prevalence of breast cancer and of post-mastectomy neuropathic pain, a clinical trial is carried out to evaluate if memantine may prevent neuropathic pain development and maintain cognitive function and quality of life in cancer patients. Methods/Design: A randomized clinical trial (NCT01536314) includes 40 women with breast cancer undergoing mastectomy at the Oncology Hospital, Clermont-Ferrand, France. Memantine (5 to 20 mg/day; n = 20) or placebo (n = 20) is administered for 4 weeks starting 2 weeks before surgery. Intensity of pain, cognitive function, quality of life and of sleep, anxiety and depression are evaluated with questionnaires. The primary endpoint is pain intensity on a 0 to 10) numerical scale at 3 months post-mastectomy. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α = 0.05. Discussion: The hypothesis of this translational approach is to confirm in patients the beneficial prophylactic effect of memantine observed in animals. Such a protective action of memantine against neuropathic pain and cognitive dysfunction would greatly improve the quality of life of cancer patients. Trial registration: ClinicalTrials.gov: NCT01536314 on 16 February 201

The brain signature of paracetamol in healthy volunteers: a double-blind randomized trial

International audienceBackground: Paracetamol’s (APAP) mechanism of action suggests the implication of supraspinal structures but no neuroimaging study has been performed in humans.Methods and results: This randomized, double-blind, crossover, placebo-controlled trial in 17 healthy volunteers (NCT01562704) aimed to evaluate how APAP modulates pain-evoked functional magnetic resonance imaging signals. We used behavioral measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli with APAP or placebo administration. Region-of-interest analysis revealed that activity in response to noxious stimulation diminished with APAP compared to placebo in prefrontal cortices, insula, thalami, anterior cingulate cortex, and periaqueductal gray matter.Conclusion: These findings suggest an inhibitory effect of APAP on spinothalamic tracts leading to a decreased activation of higher structures, and a top-down influence on descending inhibition. Further binding and connectivity studies are needed to evaluate how APAP modulates pain, especially in the context of repeated administration to patients with pain

Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids

Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (+/- SEM) age 74 +/- 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation

CANABIC: CANnabis and Adolescents: effect of a Brief Intervention on their Consumption - study protocol for a randomized controlled trial.

International audienceBACKGROUND: Cannabis is the most consumed illegal substance in France. General practitioners (GPs) are the health professionals who are most consulted by adolescents. Brief intervention (BI) is a promising care initiative for the consumption of cannabis, and could be a tool for GPs in caring for adolescents who consume cannabis. The aim of the CANABIC study is to measure the impact of a BI carried out by a GP on the consumption of cannabis by adolescents of 15 to 25 years of age. METHODS: A randomized clustered controlled trial, stratified over three areas (Auvergne, Languedoc-Roussillon, and Rhone-Alps), comparing an intervention group, which carries out the BI in consultation, and a control group, which ensures routine medical care. The main assessment criterion is the consumption of cannabis by amount of joints per month, at 12 months. The amount necessary to highlight a significant difference between the two groups of 30 % of consumption at 12 months is 250 patients (50 GPs, 5 patients per GP; risk alpha = 5 %; power = 90 %; intra-cluster correlation coefficient rho = 0.2; Hawthorne effect = 15 %; lost to follow-up rates for GPs = 10 % and for patients = 20 %). This plan is replicated for the three areas, and therefore a total of 750 patients are expected.The secondary criteria for judgment are the associated consumption of tobacco and alcohol, the perception of the consequences of consumption, and the driving of a vehicle following consumption. DISCUSSION: Research about BI for young cannabis users is underway. The aim of the CANABIC study is to validate a BI suited to adolescents who consume cannabis, which may be performed in the general practice. This would provide a tool for their treatment by a GP, which could be widely distributed during initial or further medical training.Trial registration: CANABIC is a randomized clustered trial (NCT01433692, registered 2011 Sept 12), PHRC funded: Clinical Research Hospital Program (Governmental Fund, Health Ministry). Date first patient randomized: March 2012

ETUDE CHEZ LE RAT DE L'INFLUENCE DU MAGNESIUM SUR LA SENSIBILITE AUX STIMULI NOCICEPTIFS (APPROCHES COMPORTEMENTALES ET PHARMACOALOGIQUES (DOCTORAT : NEUROPHARMACOLOGIE))

CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Effets d'une dose de charge de curcumine sur la vasoactivité artérielle du fumeur sain d'âge moyen

Le but de cette étude était de déterminer les effets de la curcumine sur la fonction endothéliale de fumeurs sains âgés de 50 à 70 ans. D'autres polyphénols comme le flavonols du cacao ou l'hespéridine de l'orange ont déjà montré des effets sur la fonction vasculaire. La curcumine, un bioactif semblant avoir des effets pléiotropes, n'a été que peu étudiée dans le champ cardiovasculaire. Nous avons proposé une étude randomisée en double aveugle et en cross-over sur 9 hommes et 9 femmes ménopausées. Les effets potentiels d'une dose orale unique de curcumine ont été évalués par une approche clinique non-invasive basée sur l'étude de la fonction endothéliale. Nous avons comparé deux méthodes actuellement standards de l'évaluation de la fonction endothéliale : la vasodilatation dépendante du débit (VDD) sur l'artère brachiale par échographie bidimensionnelle et la tonométrie artérielle périphérique (PAT). Ces deux mesures ont été réalisées avant et deux heures après l'ingestion de curcumine ou de placebo. Selon les intégrateurs de risque de Framingham et SCORE, les sujets de l'étude présentaient un risque cardiovasculaire modéré à élevé. La VDD et les paramètres du sphygmocor (réalisés à l'inclusion) étaient significativement corrélés entre eux et avec les scores de risques. Il n'y avait aucune corrélation pour l'épaisseur intima-media et les paramètres de PAT. Nous n'avons pas montré de différence significative entre la prise du placebo et de la curcumine pour le VDD (p=0,24), et le Reactive Hyperemia Index (RHI) (p=0,74), un paramètre obtenu par PAT, en grande partie à cause la forte variabilité inter-individuelle des paramètres. En complétant l'analyse statistique de façon exploratoire sur les groupes des hommes et des femmes, en raison d'une grande différence entre les sexes pur le FMD, il apparait un effet significatif de la curcumine sur le paramètre de FMD (p<0,001) chez les femmes, mais pas chez les hommes. Les résultats cliniques de cette étude ne permettent pas de conclure à un effet bénéfique de la curcumine à dose unique sur la fonction endothéliale, bien qu'une différence se dégage chez les femmes de notre population. Toutefois, des analyses complémentaires concernant la biodisponibilité de la curcumine sont nécessaires pour comprendre ces différences entre les sexes.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF