32 research outputs found
âLow-saltâ bread as an important component of a pragmatic reduced-salt diet for lowering blood pressure in adults with elevated blood pressure
Reformulation of bread in terms of salt content remains an important measure to help achieve a reduction in salt intake in the population and for the prevention of hypertension and elevated blood pressure (BP). Our fundamental studies on the reduction of salt on dough and bread characteristics showed that wheat breads produced with 0.3 g salt/100 g (âlow-saltâ) were found to be comparable quality to that produced with the typical level of salt (1.2%). This food-based intervention trial examined, using a 5 week cross-over design, the potential for inclusion of âlow-saltâ bread as part of a pragmatic reduced-salt diet on BP, markers of bone metabolism, and plasma lipids in 97 adults with slightly to moderately elevated BP. Assuming all sodium from dietary intake was excreted through the urine, the intake of salt decreased by 1.7 g/day, on average, during the reduced-salt dietary period. Systolic BP was significantly lower (by 3.3 mmHg on average; p 0.12, in all cases) in any of the urinary- or serum-based biochemical indices of calcium or bone metabolism or in plasma lipids between the two periods. In conclusion, a modest reduction in dietary salt intake, in which the use of âlow-saltâ (i.e., 0.3 g/100g) bread played a key role along with dietary advice, and led to a significant, and clinically meaningful, decrease in systolic, but not diastolic, BP in adults with mildly to moderately elevated BP
Study of pharmacokinetic parameters and the hematological toxicity of CDK4/6 inhibitors in locally advanced or metastatic breast cancers
Les inhibiteurs des CDK4/6, palbociclib et ribociclib, en association Ă lâhormonothĂ©rapie reprĂ©sentent le traitement standard de premiĂšre ligne des cancers du sein RH+/HER2- localement avancĂ©s ou mĂ©tastatiques. Les Ă©tudes de phase 3 ont mis en Ă©vidence des toxicitĂ©s hĂ©matologiques de type neutropĂ©nie de haut grade (G3-G4) chez 55% des patientes dĂšs le premier cycle de traitement. Ce type de toxicitĂ© nĂ©cessite un suivi biologique rapprochĂ© pouvant entrainer le dĂ©calage de cycle et une diminution des posologies, donc un risque potentiel dâĂ©chappement thĂ©rapeutique. Les inhibiteurs de kinase, dont font partie les inhibiteurs des CDK4/6, sont soumis Ă de nombreuses sources de variabilitĂ©s intra et interindividuelles dâorigine pharmacocinĂ©tique (PK) pouvant moduler lâexposition plasmatique et ainsi leur efficacitĂ© et leur tolĂ©rance. Le polymorphisme gĂ©nĂ©tique des dĂ©terminants du mĂ©tabolisme et du transport (pharmacogĂ©nĂ©tique, PG), les problĂšmes d'observance liĂ©s Ă la voie orale, les interactions mĂ©dicamenteuses (IM) ou encore lâĂ©tat physiopathologique des patients sont des critĂšres pouvant faire varier les paramĂštres PK des inhibiteurs de CDK4/6. La mesure de la concentration plasmatique rĂ©siduelle Ă lâĂ©quilibre en drogue est un outil pour suivre lâexposition (suivi thĂ©rapeutique pharmacologique, STP). Lâobjectif principal de lâĂ©tude clinique menĂ©e est de rechercher une corrĂ©lation entre la concentration rĂ©siduelle Ă lâĂ©quilibre du palbociclib Ă C1J15 avec la survenue dâune neutropĂ©nie de grade 3-4 pendant les deux premiers cycles de traitement, dans le cancer sein localement avancĂ© ou mĂ©tastatique RH+/HER2-. La finalitĂ© est dâidentifier (1) un intervalle de concentration pour lequel on maintient lâactivitĂ© pharmacologique tout en limitant la survenue de toxicitĂ© et (2) de pouvoir individualiser la prescription et la posologie du palbociclib en fonction de donnĂ©es PK et PG. LâĂ©tude clinique ALCINA 2 a Ă©tĂ© crĂ©Ă©e et ouverte aux inclusions sur lâInstitut du cancer de Montpellier et le CHU de NĂźmes durant la pĂ©riode 2018-2021. Nous avons mis au point et validĂ© la mĂ©thode de dosage (HPLC-MS) du palbociclib et ribociclib. La concentration rĂ©siduelle moyenne en palbociclib au C1J15 pour les 54 patientes Ă©valuables Ă©tait de 80,3 ng/ml (mĂ©diane de 74,1 ng/ml). Lâexploration de la relation entre les donnĂ©es pharmacocinĂ©tiques et la toxicitĂ© (PK/Tox) du palbociclib a mis en Ă©vidence une corrĂ©lation significative entre exposition plasmatique et survenue dâune neutropĂ©nie de haut grade (p<0,05, analyse multivariĂ©e). Lâanalyse pharmacogĂ©nĂ©tique dĂ©montre une corrĂ©lation significative entre le gĂ©notype du variant de PXR (rs10934498) et lâexposition au palbociclib (p=0,031) avec une concentration plasmatique rĂ©duite pour le gĂ©notype G/G. Par ailleurs nous avons montrĂ© que certaines co-mĂ©dications, type inhibiteurs du cytochrome P450 3A4 (CYP3A4) ou du transporteur ABCB1 (P-gp), entrainaient une augmentation significative de lâexposition plasmatique (106,1 ng/ml vs. 71,3 ng/ml, p=0,007).Il sâagit du 1er essai clinique prospectif sur lâĂ©tude de la relation PK/PG/ToxicitĂ© du palbociclib permettant ainsi de dĂ©crire une corrĂ©lation entre exposition et survenue de toxicitĂ©, et dâidentifier les sources de variabilitĂ©s relevante dont font partie les IM et la pharmacogĂ©nĂ©tique des dĂ©terminants du mĂ©tabolisme et du transport. Ainsi nos rĂ©sultats montrent que le STP et la pharmacogĂ©nĂ©tique pourraient ĂȘtre implĂ©mentĂ©es lors des consultations mĂ©dicales et pharmaceutiques dâinitiation du palbociclib comme outils de soins courant.CDK4/6 inhibitors, palbociclib and ribociclib, in combination with hormone therapy represent the standard of care for the first-line treatment of locally advanced or metastatic HR+/HER2- breast cancers. In terms of safety, phase 3 studies have revealed hematological toxicities including high-grade neutropenia (G3-G4) in 55% of cases during the first cycle of treatment. This toxicity requires a close biological monitoring, that may lead to therapeutic break and dose reduction with a potential risk of therapeutic failure. Kinase inhibitors, including CDK4/6 inhibitors, are subject of intra- and inter-individual variabilities in terms of pharmacokinetic (PK). This can directly affect the plasma concentrations of kinase inhibitor and have an impact on drug efficacy and on tolerance to the treatment. Other parameters may also affect the PK of CDK4/6 inhibitors such as the presence of specific polymorphism in genes involved in metabolism and transport (pharmacogenetic (PG) determinants), compliance problems related to the oral administration of these inhibitors, drug-drug interactions (DDI) due to associated treatments or the pathophysiological state of patients. Therapeutic Drug Monitoring (TDM) that measures plasma concentrations of the inhibitor is a pertinent tool to assess drug exposure. The main objective of our study was to investigate the potential link between the steady-state concentration of palbociclib measured at C1J15 and the occurrence of grade 3-4 neutropenia during the first two cycles of treatment in locally advanced or metastatic HR+/HER2- breast cancers. The aim was (1) to identify a concentration range for which pharmacological activity is maintained while occurrence of toxicity is limited and (2) to be able to individualize the prescription of palbociclib according to PK and PG data. To do so, the ALCINA 2 clinical trial was designed and opened to inclusions between the Montpellier Cancer Institute and the NĂźmes University Hospital (2018-2021). During the inclusions, we developed and validated the HPLC-MS assay that was used to measure palbociclib and ribociclib concentrations in the plasma. The mean residual palbociclib concentration at C1J15 for the 54 evaluable patients was 80.3 ng/mL (median 74.1 ng/mL). Exploration of the PK/Tox relationship of palbociclib showed a significant correlation between plasma concentration and occurrence of high-grade neutropenia (p<0.05, multivariate analysis). Pharmacogenetic analysis demonstrated a significant correlation between the presence of the PXR variant genotype (rs10934498) and palbociclib exposure (p=0.031) with a reduced plasma concentration for the G/G genotype. Additionally, we showed that co-medications with drugs such as CYP3A4 inhibitors or inhibitors of the ABCB1 transporter significantly increased the plasmatic exposure to palbociclib (106.1 ng/ml vs 71.3 ng/ml, p=0.007).Our study is the first prospective clinical trial on the PK/PG/Toxicity relationship of palbociclib that could identify a correlation between plasma concentration to the drug and the occurrence of toxicity. It also allowed to identify the relevant sources of variability including DDI and pharmacogenetics of metabolism and transport determinants.In conclusion, our results suggest that TDM and pharmacogenetic should be implemented in routine care during initiation of palbociclib as tools to limit pharmacokinetic variability and prevent the occurrence of high-grade neutropenia
Ătude des voies d'amĂ©lioration de la densitĂ© nutritionnelle du pain
Les cĂ©rĂ©ales et le blĂ© en particulier occupent une place de choix dans l'alimentation humaine. La consommation de pain a fortement diminuĂ© au cours des 50 derniĂšres annĂ©es et il est devenu un aliment marginal pour la couverture des apports en micronutriments dans la mesure oĂč la farine blanche a perdu la majoritĂ© de ces Ă©lĂ©ments, concentrĂ©s dans le son et le germe. L'objectif gĂ©nĂ©ral de cette thĂšse a donc Ă©tĂ© d'explorer les voies d'amĂ©lioration de la densitĂ© nutritionnelle du pain. En 1er, nous nous sommes intĂ©ressĂ©s Ă la densitĂ© nutritionnelle du blĂ©. Nous avons montrĂ© qu'il existe une variabilitĂ© gĂ©nĂ©tique significative des teneurs en minĂ©raux ainsi qu'en certains micronutriments anti-oxydants (carotĂ©noĂŻdes et vitamine E). Bien que les facteurs agronomiques et environnementaux aient une influence nette sur les teneurs en minĂ©raux, il est possible de sĂ©lectionner des variĂ©tĂ©s riches en Mg et dans une moindre mesure, riches en Zn. Le problĂšme des carotĂ©noĂŻdes Ă©tait particuliĂšrement important Ă Ă©tudier puisque la sĂ©lection de ces micronutriments a Ă©tĂ© fort nĂ©gligĂ©e dans le blĂ© tendre alors que leur teneur est beaucoup plus Ă©levĂ©e dans les espĂšces diploĂŻdes et tĂ©traploĂŻdes. Ces ancĂȘtres du blĂ© tendre prĂ©sentent non seulement des teneurs en carotĂ©noĂŻdes plus importantes mais ont aussi une faible activitĂ© lipoxygĂ©nasique, ce qui assure une meilleure conservation des carotĂ©noĂŻdes au cours de la panification. Par consĂ©quent, les voies de sĂ©lection des blĂ©s tendres doivent, comme pour le blĂ© dur, viser Ă augmenter le rapport carotĂ©noĂŻdes / activitĂ© lipoxygĂ©nasique. La 2Ăšme partie de nos travaux a concernĂ© l'impact des procĂ©dĂ©s de transformation du grain. Nous avons mis en Ă©vidence que, pour un rendement meunier identique, les farines issues de l'Ă©crasement des grains sur meules de pierre possĂšdent des teneurs minĂ©rales systĂ©matiquement supĂ©rieures (type 80) Ă celles obtenues classiquement par cisaillement entre 2 cylindres. Ceci aboutit Ă une meilleure rĂ©cupĂ©ration du germe dans la farine de meule mais aussi Ă un meilleur broyage de la couche d'aleurone. L'adaptation des diagrammes des moulins Ă cylindres est une autre alternative possible pour enrichir les farines courantes en minĂ©raux et nous avons dĂ©fendu l'hypothĂšse d'un recours Ă un fractionnement " mĂ©nagĂ© ". Une attention insuffisante a Ă©tĂ© portĂ©e Ă la rĂ©cupĂ©ration du germe et Ă la richesse du blĂ© et du pain en tocophĂ©rols, responsables de l'activitĂ© vitaminique E. Ces micronutriments sont mieux absorbĂ©s que les autres antioxydants du grain de blĂ© et donc plus efficaces dans la prĂ©vention du stress oxydant. Cette thĂšse aborde Ă©galement la question des polyphĂ©nols du blĂ© (acide fĂ©lurique du son et flavoĂŻdes du germe) et a permis de montrer que ces micronutriments antioxydants sont peu biodisponibles et ont donc un rĂŽle trĂšs secondaires dans la protection du stress oxydant. La biodisponibilitĂ© des minĂ©raux dans les produits cĂ©rĂ©aliers complets, du fait de leur richesse en acide phytique a souvent fait l'objet de controverses. C'est pourquoi nous avons recherchĂ© Ă optimiser les conditions d'hydrolyse de l'acide phytique au cours de la panification. Le rĂŽle principal de la phytase du blĂ© dans la solubilisation des minĂ©raux (en particulier du magnĂ©sium) a Ă©tĂ© mis en Ă©vidence dans des conditions de pH lĂ©gĂšrement acide correspondant Ă plusieurs modes de panification courant. L'ensemble de ces rĂ©sultats nous a permis de mettre au point une nouvelle mĂ©thode de panification en deux Ă©tapes : une " prĂ©-fermentation " Ă pH lĂ©gĂšrement acide (grĂące Ă l'ajout de levain) du blĂ© concassĂ© ou des fractions riches en fibres suivie de l'Ă©tape de panification classique. Le pain ainsi confectionnĂ© contient tous les minĂ©raux du grain sous une forme assimilable par l'organisme car l'acide phytique est hydrolisĂ© dans sa quasi-totalitĂ©. En conclusion, cette thĂšse a permis de dĂ©gager les concepts majeurs sur lesquels les acteurs de la filiĂšre blĂ©-farine-pain devraient s'appuyer pour Ćuvrer durablement dans le sens de l'amĂ©lioration de la densitĂ© nutritionnelle du pain : il s'agit des concepts de sĂ©lection intĂ©grĂ©e, de fractionnement mĂ©nagĂ© et de prĂ©fermentation dont l'originalitĂ© et la portĂ©e sont dĂ©veloppĂ©es dans la discussion de cette thĂšse. Finalement, revaloriser le pain sur le plan nutritionnel devrait avoir des consĂ©quences trĂšs positives en amont tout au long des Ă©tapes de son Ă©laboration et en aval pour une meilleure gestion de la santĂ© publique par l'alimentation.CLERMONT FD-BCIU-SantĂ© (631132104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF
Donner un nouvel avenir au pain dans le cadre dâune alimentation durable et prĂ©ventive
Times Cited: 0During a long time, the wheat-bread sector has privileged the production of a very airy white bread, and the development of traditional bread has not solved all the problems. White bread, made with flour type 55-65 has a too low nutritional value, too much salt and the nature of its gluten seems to induce in predisposed individuals non-coeliac gluten hypersensitivity. The solution to these problems would be to increase the nutritional value of bread by increasing flour type and improving gluten digestibility by a judicious choice of varieties and improved wheat baking processes. This article describes various solutions to fight against the risk of a hypersensitivity to gluten and gluten phobia it induces. Furthermore, it is proposed to diversify the supply of bread and use this essential food as an effective vehicle for a successful preventive nutrition
Sourdough fermentation of wheat fractions rich in fibres before their use in processed food
International audienceFibre-rich fractions of wheat are an important source of minerals but also contain considerable amounts of phytic acid, known to impair mineral absorption. This study explores the efficiency of wheat bran sourdough fermentation on phytate hydrolysis and mineral solubility, in comparison with whole-wheat flour. In vitro trials were performed to assess the consequences of the addition of calcium carbonate (CaCO3), an alkalinising salt, on phytic acid breakdown and mineral bioavailability during sourdough fermentation. Sourdough fermentation was found effective for solubilising minerals in whole-wheat flours but was less effective with bran. In addition, sourdough acidity was blunted by the addition of CaCO3, whereas degradation of phytic acid remained effective. Despite extensive breakdown of phytic acid (almost 70%), the addition of calcium exerted a very negative effect on zinc solubility. In conclusion, a pre-fermentation process of whole cereals or bran, in suitable conditions of hydration, allows degradation of the major part of phytic acid and optimal mineral bioavailability
Moderate Decrease of pH by Sourdough Fermentation Is Sufficient To Reduce Phytate Content of Whole Wheat Flour through Endogenous Phytase Activity
Cancer Immunotherapy Dosing: A Pharmacokinetic/Pharmacodynamic Perspective
International audienceImmune check-point inhibitors are drugs that are markedly different from other anticancer drugs because of their indirect mechanisms of antitumoral action and their apparently random effect in terms of efficacy and toxicity. This marked pharmacodynamics variability in patients calls for reconsidering to what extent approved dosing used in clinical practice are optimal or whether they should require efforts for customization in outlier patients. To better understand whether or not dosing could be an actionable item in oncology, in this review, preclinical and clinical development of immune checkpoint inhibitors are described, particularly from the angle of dose finding studies. Other issues in connection with dosing issues are developed, such as the flat dosing alternative, the putative role therapeutic drug monitoring could play, the rise of combinatorial strategies, and pharmaco-economic aspects
Genetic variability and stability of grain magnesium, zinc and iron concentrations in bread wheat
Four trials were conducted to study the grain magnesium (Mg), zinc (Zn) and iron (Fe) concentrations in bread wheat (Triticum aestivum L.). These trials used different sources of genotypes, including old French landraces, a worldwide germplasm collection and elite breeding lines or modem cultivars, grown in different environments. Mg concentration ranged from 600 to 1400 ppm in modem material, and reached 1890 ppm in some exotic genotypes. There was a negative correlation between grain yield and Mg concentration, but despite this dilution effect enough variability remains useful for selection purposes. Analysis of variance showed high genotype effects and Spearman rank correlations indicated moderate genotype by environment (G x E) interactions, so breeding for high Mg concentration can reasonably be envisaged. Zn concentration generally ranged from 15 to 35 ppm, but increased to 43 ppm in some genetic resources. Variation in Zn was also partly explained by a dilution effect. There was a significant effect of genotype, but also high G x E interactions, which would make direct selection more difficult than for Mg. However, as Zn and Mg concentrations appeared to be positively correlated, Zn concentration should respond favorably to selection for high Mg concentration. Fe concentration ranged from 20 to 60 ppm, and reached 88 ppm in non-adapted material. There were no significant genotype effects, very high G x E interactions, and the trait was poorly correlated to other mineral concentrations. Breeding for high Fe concentration will thus probably prove illusory