The role of stearic acid in ascorbic acid protection from degradation: a heterogeneous system for homogeneous thermodynamic data

International audienceA heterogeneous system between vitamin C and stearic acid was characterized by thermal and crystallographic analyses. The results showed that such a system prevents vitamin C from thermal decomposition. The evidence was provided by implementing a new protocol associating chromatic assays and thermal analyses in order to quantify the percentage of non-degraded vitamin C. The results collected with the vitamin C–stearic acid mixtures allowed deducing coherent interpretation of the results obtained with pure vitamin C at different heating scan rates. Vitamin C mainly degrades upon melting but also in the solid state for temperature close to the melting point when the heating rates are very low. Under these conditions, the temperature determined at the onset of the DSC graphs cannot be associated with the melting temperature but with a fusion-degradation phenomenon. At higher scan rates, the onset as well as the endothermic value of the signal increase to reach plateau values. These values have been identified as the temperature and enthalpy values of melting of vitamin C according to the results obtained from the heterogeneous system

Détermination des solvants résiduels dans les matières premières et produits finis pharmaceutiques

PARIS-BIUP (751062107) / SudocSudocFranceF

Thermalisme à Luxeuil-les-Bains

PARIS-BIUP (751062107) / SudocSudocFranceF

La maladie d' Alzheimer

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs

Humanization of the Blood-Brain Barrier Transporter ABCB1 in Mice Disrupts Genomic Locus - Lessons from Three Unsuccessful Approaches

ATP-binding cassette (ABC) transporters are of major importance for the restricted access of toxins and drugs to the human body. At the body's barrier tissues like the blood–brain barrier, these transporters are highly represented. Especially, ABCB1 (P-glycoprotein) has been a priority target of pharmaceutical research, for instance, to aid chemotherapy of cancers, therapy resistant epilepsy, and lately even neurodegenerative diseases. To improve translational research, the humanization of mouse genes has become a popular tool although, like recently seen for Abcb1, not all approaches were successful. Here, we report the characterization of another unsuccessful commercially available ABCB1 humanized mouse strain. In vivo assessment of transporter activity using positron emission tomography imaging revealed a severe reduction of ABCB1 function in the brain of these mice. Analyses of brain mRNA and protein expression showed that the murine Abcb1a gene is still expressed in homozygous humanized animals while expression of the human gene is minimal. Promoter region analyses underpinned that the introduced human gene might dysregulate normal expression and provided insights into the regulation of both transcription and translation of Abcb1a. We conclude that insertion of the human coding DNA sequence (CDS) into exon 3 instead of exon 2 most probably represents a more promising strategy for Abcb1a humanization

Autoxidation Kinetics of Tetrahydrobiopterin—Giving Quinonoid Dihydrobiopterin the Consideration It Deserves

In humans, tetrahydrobiopterin (H4Bip) is the cofactor of several essential hydroxylation reactions which dysfunction cause very serious diseases at any age. Hence, the determination of pterins in biological media is of outmost importance in the diagnosis and monitoring of H4Bip deficiency. More than half a century after the discovery of the physiological role of H4Bip and the recent advent of gene therapy for dopamine and serotonin disorders linked to H4Bip deficiency, the quantification of quinonoid dihydrobiopterin (qH2Bip), the transient intermediate of H4Bip, has not been considered yet. This is mainly due to its short half-life, which goes from 0.9 to 5 min according to previous studies. Based on our recent disclosure of the specific MS/MS transition of qH2Bip, here, we developed an efficient HPLC-MS/MS method to achieve the separation of qH2Bip from H4Bip and other oxidation products in less than 3.5 min. The application of this method to the investigation of H4Bip autoxidation kinetics clearly shows that qH2Bip’s half-life is much longer than previously reported, and mostly longer than that of H4Bip, irrespective of the considered experimental conditions. These findings definitely confirm that an accurate method of H4Bip analysis should include the quantification of qH2Bip