Thesis (Ph. D.)--Columbia University, 1927. / Vita. Bibliography: p. [19].

Thesis--Aarhus. / Summary in English and Danish. Bibliography: p. [139]-145.

Thesis--Aarhus. / Summary in English and Danish. Bibliography: p. [139]-145.

A Thesis Presented in Part Fulfilment of the Requirements for the Degree of Master of Medicine in Pathology at the University of the Witwatersrand. November, 1963. / Modern pathology is forced to deal more and more with changes brought about by modern therapy on the one hand and by the abuse of drugs by the laity on the other ^ New diseases have been added, others altered. Skin allergies, collagen diseases, frightening foetal abnormalities due to thalidomide, peptic ulceration with cortison therapy are but a few of the end results of the abuse of the numerous pharmaceutical substances available with or without prescription to the public. To this list may be added the nephrotoxic effects of phena- cetin. / IT2018

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains vii, 105 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 92-105).

No / The kinetics of the dissociation is fundamental to the formation and the in vivo performance of cyclodextrin supramolecules. The individual determination of the apparent dissociation rate constant (kd,app) using high performance affinity chromatography (HPAC) is a tedious process requiring numerous separate studies and massive data fitting. In this study, the multianalyte approach was employed to simultaneously measure the kd,app values of three drugs through one injection based on the investigation of the dependence of drug-cyclodextrin interaction kinetics on the mobile phase composition. As a result, the kd,app values increased when decreasing the ion strength, increasing the ionization of drugs and adding extra organic solvents. The values of kd,app for acetaminophen, phenacetin and S-flurbiprofen estimated by the multianalyte approach were 8.54+/-1.81, 5.36+/-0.94 and 0.17+/-0.02s(-1), respectively, which were in good agreement with those determined separately (8.31+/-0.58, 5.01+/-0.42 and 0.15+/-0.01s(-1)). For both of the single and multiple flow rate peak profiling methods, the results of the multianalyte approach were statistically equivalent with that of the single compound analysis for all of the three drugs (p>0.05). The multianalyte approach can be employed for the efficient evaluation of the drug-cyclodextrin kinetics with less variance caused by cyclodextrin column bleeding.

Le développement de méthodes in vitro fiables et prédictives représente à l’heure actuelle un véritable défi. En effet, la demande en méthodes alternatives à l’expérimentation animale n’a cessé de croître ces dernières années du fait de la mise en place de législations limitant par considérations éthiques l’utilisation de ces modèles in vivo. De plus, ce besoin a été renforcé par le règlement européen REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) imposant aux industriels de valider l’innocuité de nombreuses substances déjà commercialisées. Toutefois, les modèles in vitro classiques consistant en la culture simple de cellules en monocouche dans des boîtes de Petri ne permettent pas de conserver les propriétés initiales de ces cellules et de retranscrire les conditions et l’environnement cellulaire des organes in vivo. Le développement de méthodes alternatives in vitro prédictives s’avèrent donc crucial en particulier pour mimer le fonctionnement de deux organes : l’intestin et le foie. En effet, ces deux organes sont largement impliqués dans les processus d’Absorption, Distribution, Métabolisme et Excrétion (ADME) de la plupart des xénobiotiques ingérés. C’est pour ces raisons que nous avons testé la faisabilité de l’une de ces méthodes in vitro alternative permettant d’associer une barrière intestinale à la culture dynamique de cellules hépatiques au sein de microsystèmes dans le cadre de ce doctorat. Cette coculture est effectuée au sein du dispositif appelé IIDMP (Integrated Insert in a Dynamic Microfluidic Platform). Nous avons décidé de tester d’une part l’influence de la culture dynamique et d’autre part d’éventuelles interactions entre les cellules intestinales et hépatiques sur la fonctionnalité et l’activité métabolique de ces deux types cellulaires. Les résultats obtenus durant ce doctorat ont permis d’atteindre 4 objectifs :- Développer un dispositif fiable en termes de fonctionnalité (fluidique, robustesse…).- Mettre en évidence l’innocuité du dispositif lorsque des cellules de lignée et primaires y étaient cultivées.- Démontrer les avantages de l’utilisation de ce dispositif comparativement à l’utilisation de modèles classiques in vitro, en particulier avec des cellules de lignée.- Démontrer que l’utilisation de ce dispositif permettait de mettre en évidence des phénomènes d’interactions entre cellules intestinales et hépatiques notamment sur l’activité du CYP1A2 des hépatocytes qu’ils soient issus d’une lignée ou de cultures primaires. / The development of reliable and predictive in vitro methods is a real challenge. Indeed, the demand for alternative methods to animal experimentation has been growing in recent years due to the introduction of legislation limiting the use of these models in vivo by ethical considerations. Moreover, this need was amplified by regulations such as the European REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) requiring the safety validation of many substances. However, the conventional in vitro model consisting in a simple cell culture monolayer in Petri dishes does not preserve the initial properties of these cells and does not mimic the conditions of the cellular environment and organs in vivo. The development of alternative in vitro predictive methods is crucial especially to mimic the working of two organs: the intestine and liver. Indeed, these two organs are involved in the process of Absorption, Distribution, Metabolism and Excretion (ADME) of most xenobiotics ingested.We propose in this thesis to test the feasibility of one of these in vitro alternative methods allowing the association between an intestinal barrier and the dynamic culture of hepatic cells in microsystems in a device called IIDMP (Integrated Dynamic Insert in a Microfluidic Platform). We tested the influence of the flow of culture and possible interactions between intestinal and liver cells on the function and metabolic activity of these two cell types.Then, we demonstrated that : - This device is reliable in terms of global functionality (fluid, robustness ...).- This device did not injury the integrity of the cell line and primary cells.- The use of this device has many advantages when compared with the use of conventional in vitro models, especially with cells line.- The use of this device highlights phenomena of interaction between hepatic and intestinal cells as an increase of the CYP1A2 activity of HepG2 C3A and human primary hepatocytes.