15 research outputs found
Suivi thĂ©rapeutique pharmacologique des 6-thioguanine nuclĂ©otides dans les leucĂ©mies aigues lymphoblastiques de lâenfant : intĂ©rĂȘt et limites
La 6-mercaptopurine ou 6-MP (PurinetholŸ) est une molécule cytostatique incluse dans
tous les protocoles de traitement des leucĂ©mies aigĂŒes lymphoblastiques de lâadulte et
lâenfant. Câest une prodrogue mĂ©tabolisĂ©e par plusieurs enzymes : 1- la thiopurine
S-méthyltransférase (TPMT) est une enzyme clef de son métabolisme, permettant la synthÚse
de la 6-mĂ©thylmercaptopurine (6-MMPN), 2- la xanthine oxidase (XO) permet lâinactivation
de la 6-MP en acide 6-thiourique, 3- lâhypoxanthine guanine phosphoribosyl transferase
(HGPRT) permet lâĂ©tape initiale dâanabolisme conduisant au 6-thioinosine monophosphate,
secondairement activĂ© en 6-thioguanine nucleotides (6-TGN) qui sont incorporĂ©s Ă lâADN, ou
mĂ©tabolisĂ©s en 6-thioinosine triphosphate (TITP), rĂ©action rĂ©alisĂ©e par lâinosine
triphosphate pyrophosphatase (ITPA). LâactivitĂ© TPMT est sous contrĂŽle pharmacogĂ©nĂ©tique,
de nombreuses mutations ayant été identifiées. En cas de traitement à dose standard, les
sujets avec une activité TPMT élevée (homozygotes sauvages : 90 %) ont des concentrations
plus basses de 6-TGN intra-érythrocytaires que les sujets hétérozygotes ou homozygotes
mutĂ©s. Ă lâinverse, les concentrations de 6-TGN sont Ă©levĂ©es chez les patients homozygotes
mutés qui présentent un risque élevé de toxicité, en particulier de type aplasie
mĂ©dullaire grave, si la posologie de la 6-MP nâest pas adaptĂ©e au phĂ©notype (activitĂ© TPMT
intra-érythrocytaire) ou au génotype TPMT. Enfin, les sujets hétérozygotes mutés
présentent une meilleure survie que les patients de génotype sauvage mais une augmentation
du risque de survenue de neutropénies et thrombopénies aux doses standard de thiopurines.
Afin de personnaliser le traitement par 6-MP, il est essentiel de génotyper les patients
avant lâinstauration du traitement afin de prĂ©venir les toxicitĂ©s sĂ©vĂšres chez les
homozygotes mutĂ©s, dâadapter la posologie de 6-MP au gĂ©notype et de prendre en compte les
interactions médicamenteuses. En complément de la surveillance hématologique actuellement
pratiquée, le suivi thérapeutique pharmacologique repose sur les concentrations
plasmatiques des métabolites des thiopurines (les 6-thioguanine nucléotides ou 6-TGN) et
le rapport des 6TGN/dérivés méthylés tous deux associés à la réponse aux thiopurines chez
les enfants atteints de LAL
Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats
International audienceBackground:Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects,mental retardation and non-genetic sensorineural hearing loss. Murine models have beendeveloped in order to understand the pathophysiological mechanisms underlying theselesions. These models are being proposed for the validation of therapeutic protocols forclinical use. The aim of this preclinical study was to assess the pharmacokinetics of thereference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm thediffusion of the molecule to the appropriate target zones.Methods:Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats.Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days ofintraperitoneal injection of ganciclovir. The occurrence of hematological side effects ofganciclovir was evaluated in the different blood cell lineages.Results:In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the sameconcentration as in blood. In gestating mice, transplacental diffusion was observed, with afetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile ofganciclovir showed a peak at 2 hours followed by a gradual decrease. In adult mice, theconcentration peaked at 1 hour, but became undetectable by 2 hours after injection. Counts of white blood cells, red blood cells and platelets decreased significantly inganciclovir-treated newborn mice.Conclusion:Our data provide evidence for the intracochlear diffusion of the molecule, which may berelevant for the treatment of sensorineural hearing loss in congenitally-infected children
Spirulina (<i>Arthrospira platensis</i>) Improved Nonalcoholic Fatty Liver Disease Characteristics and Microbiota and Did Not Affect Organ Fibrosis Induced by a Fructose-Enriched Diet in Wistar Male Rats
Spirulina (Arthrospira platensis) is reported to play a role in improving nonalcoholic fatty liver disease (NAFLD) and intestinal microbiota (IM). To study spirulinaâs effects in the improvement of NAFLD characteristics, IM, and pancreaticârenal lesions induced by a fructose-enriched diet, 40 Wistar healthy male rats, weighing 200â250 g, were randomly divided into four groups of 10, and each rat per group was assigned a diet of equal quantities (20 g/day) for 18 weeks. The first control group (CT) was fed a standardized diet, the second group received a 40% fructose-enriched diet (HFr), and the third (HFr-S5) and fourth groups (HFr-S10) were assigned the same diet composition as the second group but enriched with 5% and 10% spirulina, respectively. At week 18, the HFr-S10 group maintained its level of serum triglycerides and had the lowest liver fat between the groups. At the phylae and family level, and for the same period, the HFr-S10 group had the lowest increase in the Firmicutes/Bacteroidetes ratio and the Ruminococcaceae and the highest fecal alpha diversity compared to all other groups (p < 0.05). These findings suggest that at a 10% concentration, spirulina could be used in nutritional intervention to improve IM, fatty liver, metabolic, and inflammatory parameters associated with NAFLD