Colonic movements in healthy subjects as monitored by a Magnet Tracking System

Rapport de synthèse : Le Magnet Tracking System (MTS) est une technique peu invasive d'investigation de la motilité de l'entier du tube digestif. Elle repose sur le suivi de la progression d'un aimant par des senseurs externes en temps réel et dans les 3 dimensions. Dans cette étude, le MTS a été utilisé pour étudier les caractéristiques de propulsion propres aux différents segments coliques ainsi que pour comparer le transit de l'aimant permanent du MTS à celui de marqueurs radioopaques habituellement utilisés. Dix hommes et 10 femmes ayant un transit gastro-intestinal régulier ont ingéré simultanément un aimant de MTS et une capsule contenant 10 marqueurs radio-opaques, à 20h00. Les enregistrements se sont ensuite déroulés sur 2 matinées successives de 5 heures. L'analyse des données brutes recueillies a permis de réaliser une projection spatio-temporelle de la trajectoire de l'aimant dans le tube digestif ainsi qu'une description précise de l'origine, de la direction, de l'amplitude et de la vitesse des mouvements coliques. Des radiographies d'abdomen ont permis de comparer les positions respectives des marqueurs radio-opaques et de l'aimant du MTS. Durant 90% du temps d'enregistrement, l'aimant était immobile ou présentait des mouvements alternatifs de faible amplitude. Le reste des enregistrements consiste en activité propulsive dont 20% représentent des déplacements rétrogrades et une description très précise de 34 mouvements de masses. L'analyse des déplacements démontre une distribution bimodales des vitesses voisine de 1.5 et 50 cm /min, ce tant en direction orale que caudale. Deux tiers des distances parcourues le sont à vitesse rapide. L'analyse segmentaire confirme une progression horaire absolue supérieure dans le côlon gauche que droit. L'analyse détaillée par segment colique, reposant sur la description des déplacements enregistrés correspond aux rôles reconnus des différents segments, notamment de aire de stockage et de conditionnement du côlon ascendant ou de transit du côlon descendant. La comparaison des 2 sexes démontre un nombre plus important de mouvements, particulièrement de mouvements de masse chez l'homme. Les radiographies montrent une bonne corrélation entre la position de l'aimant et celle des marqueurs radio-opaques. Le MTS permet ainsi une description précise des caractéristiques propulsives des différents segments coliques, notamment par l'analyse détaillée des progressions à vitesses lente et rapide et leurs directions. Des distinctions peuvent également être notées en fonction du sexe. Ces investigations offrent de nouvelles perspectives pour l'étude des troubles de la motilité digestive.

Fractional hepatic de novo lipogenesis in healthy subjects during near-continuous oral nutrition and bed rest: a comparison with published data in artificially fed, critically ill patients.

BACKGROUND AND AIMS: In critically ill patients, fractional hepatic de novo lipogenesis increases in proportion to carbohydrate administration during isoenergetic nutrition. In this study, we sought to determine whether this increase may be the consequence of continuous enteral nutrition and bed rest. We, therefore, measured fractional hepatic de novo lipogenesis in a group of 12 healthy subjects during near-continuous oral feeding (hourly isoenergetic meals with a liquid formula containing 55% carbohydrate). In eight subjects, near-continuous enteral nutrition and bed rest were applied over a 10 h period. In the other four subjects, it was extended to 34 h. Fractional hepatic de novo lipogenesis was measured by infusing(13) C-labeled acetate and monitoring VLDL-(13)C palmitate enrichment with mass isotopomer distribution analysis. Fractional hepatic de novo lipogenesis was 3.2% (range 1.5-7.5%) in the eight subjects after 10 h of near continuous nutrition and 1.6% (range 1.3-2.0%) in the four subjects after 34 h of near-continuous nutrition and bed rest. This indicates that continuous nutrition and physical inactivity do not increase hepatic de novo lipogenesis. Fractional hepatic de novo lipogenesis previously reported in critically ill patients under similar nutritional conditions (9.3%) (range 5.3-15.8%) was markedly higher than in healthy subjects (P<0.001). These data from healthy subjects indicate that fractional hepatic de novo lipogenesis is increased in critically ill patients.

Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects.

The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of <or= 5 mg.

The effect of ethanol on fat storage in healthy subjects.

BACKGROUND: Ethanol can account for up to 10 percent of the energy intake of persons who consume moderate amounts of ethanol. Its effect on energy metabolism, however, is not known. METHODS: We studied the effect of ethanol on 24-hour substrate-oxidation rates in eight normal men during two 48-hour sessions in an indirect-calorimetry chamber. In each session, the first 24 hours served as the control period. On the second day of one session, an additional 25 percent of the total energy requirement was added as ethanol (mean [+/- SD], 96 +/- 4 g per day); during the other session, 25 percent of the total energy requirement was replaced by ethanol, which was isocalorically substituted for lipids and carbohydrates. RESULTS: Both the addition of ethanol and the isocaloric substitution of ethanol for other foods reduced 24-hour lipid oxidation. The respective mean (+/- SE) decreases were 49.4 +/- 6.7 and 44.1 +/- 9.3 g per day (i.e., reductions of 36 +/- 3 percent and 31 +/- 7 percent from the oxidation rate during the control day; P less than 0.001 and P less than 0.0025). This effect occurred only during the daytime period (8:30 a.m. to 11:30 p.m.), when ethanol was consumed and metabolized. Neither the addition of ethanol to the diet nor the isocaloric substitution of ethanol for other foods significantly altered the oxidation of carbohydrate or protein. Both regimens including ethanol produced an increase in 24-hour energy expenditure (7 +/- 1 percent with the addition of ethanol, P less than 0.001; 4 +/- 1 percent with the substitution of ethanol for other energy sources, P less than 0.025). CONCLUSIONS: Ethanol, either added to the diet or substituted for other foods, increases 24-hour energy expenditure and decreases lipid oxidation. Habitual consumption of ethanol in excess of energy needs probably favors lipid storage and weight gain.

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil.

To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects. Prospective, sequential investigation comparing three different FO doses. Three groups of male subjects aged 26.8 +/- 3.2 years (BMI 22.5 +/- 2.1). One of three FO doses (Omegaven10%) as a slow infusion before LPS: 0.5 g/kg 1 day before LPS, 0.2 g/kg 1 day before, or 0.2 g/kg 2 h before. Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-alpha, stress hormones) were collected. After LPS temperature, ACTH and TNF-alpha concentrations increased in the three groups: the responses were significantly blunted (p < 0.0001) compared with the control group of the Pluess et al. trial. Cortisol was unchanged. Lowest plasma ACTH, TNF-alpha and temperature AUC values were observed after a single 0.2 g/kg dose of FO. EPA incorporation into platelet membranes was dose-dependent. Having previously shown that the response to LPS was reproducible, this study shows that three FO doses blunted it to various degrees. The 0.2 g/kg perfusion immediately before LPS was the most efficient in blunting the responses, suggesting LPS capture in addition to the systemic and membrane effects.

Higher memory responses in HIV-infected and kidney transplanted patients than in healthy subjects following priming with the pandemic vaccine.

BACKGROUND: Memory responses require immune competence. We assessed the influence of priming with AS03-adjuvanted pandemic vaccine (Pandemrix®) on memory responses of HIV patients, kidney recipients (SOT) and healthy controls (HC). METHOD: Participants (HIV: 197, SOT: 53; HC: 156) were enrolled in a prospective study and 390/406 (96%) completed it. All had been primed in 2009/2010 with 1 (HC) or 2 (patients) doses of Pandemrix®, and were boosted with the 2010/2011 seasonal influenza vaccine. Geometric mean titres and seroprotection rates were measured 12 months after priming and 4 weeks after boosting. Primary and memory responses were directly compared in 191 participants (HCW: 69, HIV: 71, SOT: 51) followed during 2 consecutive seasons. RESULTS: Most participants (HC: 77.8%, HIV: 77.6%, SOT: 66%) remained seroprotected at 12 months post-priming. Persisting A/09/H1N1 titers were high in HIV (100.2) and HC (120.1), but lower in SOT (61.4) patients. Memory responses reached higher titers in HIV (507.8) than in HC (253.5) and SOT (136.9) patients. Increasing age and lack of HAART reduced persisting and memory responses, mainly influenced by residual antibody titers. Comparing 2009/2010 and 2010/2011 titers in 191 participants followed for 2 seasons indicated lower post-2010/2011 titers in HC (240.2 vs 313.9), but higher titers in HIV (435.7 vs 338.0) and SOT (136 vs 90.3) patients. CONCLUSIONS: Priming with 2 doses of Pandemrix® elicited persistent antibody responses and even stronger memory responses to non-adjuvanted seasonal vaccine in HIV patients than 1 dose in healthy subjects. Adjuvanted influenza vaccines may improve memory responses of immunocompromised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01022905.

Targetting of the ventro-intermediate nucleus using ultra-high field (7T) MRI for gamma knife surgery purposes: A pilot in vivo study on healthy subjects.

INTRODUCTION: Gamma Knife surgery (GKS) is a non-invasive neurosurgical stereotactic procedure, increasingly used as an alternative to open functional procedures. This includes targeting of the ventro-intermediate nucleus of the thalamus (e.g. Vim) for tremor. We currently perform an indirect targeting, as the Vim is not visible on current 3Tesla MRI acquisitions. Our objective was to enhance anatomic imaging (aiming at refining the precision of anatomic target selection by direct visualisation) in patients treated for tremor with Vim GKS, by using high field 7T MRI. MATERIALS AND METHODSH: Five young healthy subjects were scanned on 3 (T1-w and diffusion tensor imaging) and 7T (high-resolution susceptibility weighted images (SWI)) MRI in Lausanne. All images were further integrated for the first time into the Gamma Plan Software(®) (Elekta Instruments, AB, Sweden) and co-registered (with T1 was a reference). A simulation of targeting of the Vim was done using various methods on the 3T images. Furthermore, a correlation with the position of the found target with the 7T SWI was performed. The atlas of Morel et al. (Zurich, CH) was used to confirm the findings on a detailed analysis inside/outside the Gamma Plan. RESULTS: The use of SWI provided us with a superior resolution and an improved image contrast within the basal ganglia. This allowed visualization and direct delineation of some subgroups of thalamic nuclei in vivo, including the Vim. The position of the target, as assessed on 3T, perfectly matched with the supposed one of the Vim on the SWI. Furthermore, a 3-dimensional model of the Vim-target area was created on the basis of the obtained images. CONCLUSION: This is the first report of the integration of SWI high field MRI into the LGP, aiming at the improvement of targeting validation of the Vim in tremor. The anatomical correlation between the direct visualization on 7T and the current targeting methods on 3T (e.g. quadrilatere of Guyot, histological atlases) seems to show a very good anatomical matching. Further studies are needed to validate this technique, both by improving the accuracy of the targeting of the Vim (potentially also other thalamic nuclei) and to perform clinical assessment.

MOBP-specific cellular immune responses are weaker than MOG-specific cellular immune responses in patients with multiple sclerosis and healthy subjects.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Myelin oligodendrocyte glycoprotein (MOG) and myelin oligodendrocyte basic protein (MOBP) were both shown to be highly encephalitogenic in animal models of MS. In contrast, the association of MOG- and MOBP-specific humoral or cellular immune responses and MS in humans is far less established. In this study, we sought to analyse MOG- and MOBP-specific T-cell responses in a large cohort of patients with various stages of the disease. Patients with other neurological diseases and healthy subjects were enrolled to serve as control study subjects. We determined the proliferation and the secretion of IFN-γ secretion in our cohort. We found that MOG-specific T-cell responses were higher and more frequent as compared to MOBP-specific ones. However, both MS patients and control study subjects had similar myelin-specific T-cell responses at the periphery, thus calling for more precise studies at CNS level.

Transforming growth factor beta 1 production by CD4+ CD25+ regulatory T cells in peripheral blood mononuclear cells from healthy subjects stimulated with Leishmania guyanensis.

Transforming growth factor beta (TGF-beta) has been shown to be a central immunomodulator used by leishmaniae to escape effective mechanisms of protection in human and murine infections with these parasites. However, all the information is derived from studies of established infection, while little is known about TGF-beta production in response to Leishmania stimulation in healthy subjects. In this study, TGF-beta1 production was demonstrated in peripheral blood mononuclear cells from healthy subjects never exposed to leishmaniae in response to live Leishmania guyanensis, and the TGF-beta1-producing cells were described as a distinct subpopulation of CD4(+) CD25(+) regulatory T cells. The suppressive properties of CD4(+) CD25(+) T cells were demonstrated in vitro by their inhibition of production of interleukin 2 (IL-2) and IL-10 by CD4(+) CD25(-) T cells in the presence of either anti-CD3 or L. guyanensis. Although neutralization of TGF-beta1 did not reverse the suppressive activity of CD4(+) CD25(+) T cells activated by anti-CD3, it reversed the suppressive activity of CD4(+) CD25(+) T cells activated by L. guyanensis. Altogether our data demonstrated that TGF-beta1 is involved in the suppressive activity of L. guyanensis-stimulated CD4(+) CD25(+) T cells from healthy controls.

Decoding decisions in healthy subjects and auditory discrimination in comatose patients through single-trial topographic EEG analyses

Neuroimaging studies analyzing neurophysiological signals are typically based on comparing averages of peri-stimulus epochs across experimental conditions. This approach can however be problematic in the case of high-level cognitive tasks, where response variability across trials is expected to be high and in cases where subjects cannot be considered part of a group. The main goal of this thesis has been to address this issue by developing a novel approach for analyzing electroencephalography (EEG) responses at the single-trial level. This approach takes advantage of the spatial distribution of the electric field on the scalp (topography) and exploits repetitions across trials for quantifying the degree of discrimination between experimental conditions through a classification scheme. In the first part of this thesis, I developed and validated this new method (Tzovara et al., 2012a,b). Its general applicability was demonstrated with three separate datasets, two in the visual modality and one in the auditory. This development allowed then to target two new lines of research, one in basic and one in clinical neuroscience, which represent the second and third part of this thesis respectively. For the second part of this thesis (Tzovara et al., 2012c), I employed the developed method for assessing the timing of exploratory decision-making. Using single-trial topographic EEG activity during presentation of a choice's payoff, I could predict the subjects' subsequent decisions. This prediction was due to a topographic difference which appeared on average at ~516ms after the presentation of payoff and was subject-specific. These results exploit for the first time the temporal correlates of individual subjects' decisions and additionally show that the underlying neural generators start differentiating their responses already ~880ms before the button press. Finally, in the third part of this project, I focused on a clinical study with the goal of assessing the degree of intact neural functions in comatose patients. Auditory EEG responses were assessed through a classical mismatch negativity paradigm, during the very early phase of coma, which is currently under-investigated. By taking advantage of the decoding method developed in the first part of the thesis, I could quantify the degree of auditory discrimination at the single patient level (Tzovara et al., in press). Our results showed for the first time that even patients who do not survive the coma can discriminate sounds at the neural level, during the first hours after coma onset. Importantly, an improvement in auditory discrimination during the first 48hours of coma was predictive of awakening and survival, with 100% positive predictive value. - L'analyse des signaux électrophysiologiques en neuroimagerie se base typiquement sur la comparaison des réponses neurophysiologiques à différentes conditions expérimentales qui sont moyennées après plusieurs répétitions d'une tâche. Pourtant, cette approche peut être problématique dans le cas des fonctions cognitives de haut niveau, où la variabilité des réponses entre les essais peut être très élevéeou dans le cas où des sujets individuels ne peuvent pas être considérés comme partie d'un groupe. Le but principal de cette thèse est d'investiguer cette problématique en développant une nouvelle approche pour l'analyse des réponses d'électroencephalographie (EEG) au niveau de chaque essai. Cette approche se base sur la modélisation de la distribution du champ électrique sur le crâne (topographie) et profite des répétitions parmi les essais afin de quantifier, à l'aide d'un schéma de classification, le degré de discrimination entre des conditions expérimentales. Dans la première partie de cette thèse, j'ai développé et validé cette nouvelle méthode (Tzovara et al., 2012a,b). Son applicabilité générale a été démontrée avec trois ensembles de données, deux dans le domaine visuel et un dans l'auditif. Ce développement a permis de cibler deux nouvelles lignes de recherche, la première dans le domaine des neurosciences cognitives et l'autre dans le domaine des neurosciences cliniques, représentant respectivement la deuxième et troisième partie de ce projet. En particulier, pour la partie cognitive, j'ai appliqué cette méthode pour évaluer l'information temporelle de la prise des décisions (Tzovara et al., 2012c). En se basant sur l'activité topographique de l'EEG au niveau de chaque essai pendant la présentation de la récompense liée à un choix, on a pu prédire les décisions suivantes des sujets (en termes d'exploration/exploitation). Cette prédiction s'appuie sur une différence topographique qui apparaît en moyenne ~516ms après la présentation de la récompense. Ces résultats exploitent pour la première fois, les corrélés temporels des décisions au niveau de chaque sujet séparément et montrent que les générateurs neuronaux de ces décisions commencent à différentier leurs réponses déjà depuis ~880ms avant que les sujets appuient sur le bouton. Finalement, pour la dernière partie de ce projet, je me suis focalisée sur une étude Clinique afin d'évaluer le degré des fonctions neuronales intactes chez les patients comateux. Des réponses EEG auditives ont été examinées avec un paradigme classique de mismatch negativity, pendant la phase précoce du coma qui est actuellement sous-investiguée. En utilisant la méthode de décodage développée dans la première partie de la thèse, j'ai pu quantifier le degré de discrimination auditive au niveau de chaque patient (Tzovara et al., in press). Nos résultats montrent pour la première fois que même des patients comateux qui ne vont pas survivre peuvent discriminer des sons au niveau neuronal, lors de la phase aigue du coma. De plus, une amélioration dans la discrimination auditive pendant les premières 48heures du coma a été observée seulement chez des patients qui se sont réveillés par la suite (100% de valeur prédictive pour un réveil).

Noninvasive visualization of coronary artery endothelial function in healthy subjects and in patients with coronary artery disease.

OBJECTIVES: The goal was to test 2 hypotheses: first, that coronary endothelial function can be measured noninvasively and abnormal function detected using clinical 3.0-T magnetic resonance imaging (MRI); and second, that the extent of local coronary artery disease (CAD), in a given patient, is related to the degree of local abnormal coronary endothelial function. BACKGROUND: Abnormal endothelial function mediates the initiation and progression of atherosclerosis and predicts cardiovascular events. However, direct measures of coronary endothelial function have required invasive assessment. METHODS: The MRI was performed in 20 healthy adults and 17 patients with CAD. Cross-sectional coronary area and blood flow were quantified before and during isometric handgrip exercise, an endothelial-dependent stressor. In 10 severe, single-vessel CAD patients, paired endothelial function was measured in the artery with severe stenosis and the contralateral artery with minimal disease. RESULTS: In healthy adults, coronary arteries dilated and flow increased with stress. In CAD patients, coronary artery area and blood flow decreased with stress (both p </= 0.02). In the paired study, coronary artery area and blood flow failed to increase during exercise in the mildly diseased vessel, but both area (p = 0.01) and blood flow (p = 0.02) decreased significantly in the severely diseased, contralateral artery. CONCLUSIONS: Endothelial-dependent coronary artery dilation and increased blood flow in healthy subjects, and their absence in CAD patients, can now be directly visualized and quantified noninvasively. Local coronary endothelial function differs between severely and mildly diseased arteries in a given CAD patient. This novel, safe method may offer new insights regarding the importance of local coronary endothelial function and improved risk stratification in patients at risk for and with known CAD.

Effects of lactate on glucose metabolism in healthy subjects and in severely injured hyperglycemic patients.

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects

Enjeu : L'incidence d'insuffisance rénale terminale augmente d'environ 5-6% par année dans nos régions. L'une des causes majeures d'insuffisance rénale est la néphropathie diabétique qui représente selon les pays entre 25 et 40% des néphropathies terminales. La progression de la néphropathie diabétique peut être ralentie de manière efficace par un bon contrôle du diabète et de l'hypertension artérielle et par le blocage du système rénine-angiotensine. Néanmoins, malgré l'application stricte de ces thérapies préventives, la néphropathie de bons nombres de patients diabétiques continue de progresser. Il est donc important de développer de nouvelles stratégies permettant de préserver la fonction rénale des patients diabétiques soit en améliorant le contrôle de la pression artérielle soit en diminuant la protéinurie. Contexte : Il existe un certain nombre d'évidences expérimentales que le blocage des récepteurs de l'endothéline pourrait avoir un effet positif sur le devenir de la néphropathie diabétique en diminuant de manière efficace la protéinurie même chez des animaux déjà traités efficacement avec un bloqueur du système rénine-angiotensine. Dans des études de phase 2 impliquant l'avosentan, un antagoniste des récepteurs de l'endothéline actuellement en cours de développement pour le traitement de la néphropathie diabétique, on a pu démontrer que cet antagoniste, prescrit à des doses oscillant entre 5 et 50 mg par jour per os, diminue la protéinurie d'environ 20-40% chez des patients déjà traités avec un IEC ou un antagoniste de l'angiotensine. Toutefois, une grande étude de phase III conduite avec ce médicament chez des patients diabétiques a du être interrompue précocement en raison de l'apparition d'oedèmes et d'une surcharge hydrosodée conduisant dans certains cas à une décompensation cardiaque aiguë. La rétention hydrosodée est un effet secondaire connu des antagonistes de l'endothéline déjà sur le marché. Toutefois, pour l'avosentan, on ne savait pas si des doses plus faibles du médicament avaient aussi un effet négative sur la balance hydrosodée. En outre, les mécanismes rénaux responsables de la rétention hydrosodée sont encore mal connus chez l'homme. C'est pourquoi, nous avons organisé et réalisé cette étude de pharmacologie clinique chez le volontaire sain posant 2 questions : 1) des doses faibles d'avosentan produisent-elles aussi une rétention hydrosodée chez l'homme ? et 2) quels sont les mécanismes rénaux pouvant expliquer la rétention hydrosodée ? Cette thèse est donc une étude clinique de phase I testant chez 23 volontaires sains les effets rénaux de différentes doses d'avosentan ou d'un placebo pour établir la courbe dose-réponse des effets rénaux de ce médicament. L'idée était également de définir quelle dose est sure et bien tolérée pour être utilisée dans une nouvelle étude de phase II. L'avosentan a été administré par voie orale une fois par jour pendant 8 jours à des doses de 0.5, 1.5, 5 et 50 mg. Les effets rénaux hémodynamiques et tubulaires ont été étudiés chez chaque sujet lors de la première administration (jour 1) et après une semaine de traitement (jour 8). Le médicament a induit une prise de poids dose-dépendante déjà présente à 5 mg et maximale à 50 mg (+ 0.8 kg au jour 8). Nous n'avons pas mesuré d'impact de l'avosentan sur l'hémodynamique rénale ni sur les électrolytes plasmatiques. En revanche, nous avons constaté une diminution dose-dépendante de la fraction d'excrétion de sodium (jusqu'à -8.7% avec avosentan 50 mg). Cette diminution était en rapport avec une augmentation dose-dépendante de la réabsorption proximale de sodium. Nous avons également constaté une baisse de la pression artérielle aux doses élevées et une hémodilution marquée par une baisse de l'hématocrite suggérant une rétention hydrique à la plus haute dose. Nos résultats suggèrent donc que l'avosentan induit une rétention sodée rénale dose-dépendante expliquée avant tout par une rétention du sodium au niveau du tubule proximal. Cet effet n'est pas observé à des doses plus basses que 5 mg chez le volontaire sain, suggérant que ce médicament devrait être évalué pour son activité réno-protectrice à des doses inférieures ou égales à 5 mg par jour. La raison pour laquelle les hautes doses produisent plus de rétention sodée est peut être liée à une perte de sélectivité pour les sous-types (A et B) de récepteurs à l'endothéline lorsque l'on administre des doses plus élevées que 5 mg. Perspectives : Les résultats de ce travail de thèse ont donc permis de caractériser les propriétés rénales d'un nouvel antagoniste des récepteurs de l'endothéline chez l'homme. Ces résultats ont aussi permis de guider le développement futur de ce médicament vers des doses plus faibles avec l'espoir de garder les effets bénéfiques sur la protéinurie tout en améliorant le profil de tolérance du médicament par l'utilisation de doses plus faibles. ANGLAIS The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of ≤ 5 mg.

Colonic movements in healthy subjects as monitored by a Magnet Tracking System.

The Magnet Tracking System (MTS) is a minimally-invasive technique of continuous evaluation of gastrointestinal motility. In this study, MTS was used to analyse colonic propulsive dynamics and compare the transit of a magnetic pill with that of standard radio-opaque markers. MTS monitors the progress in real time of a magnetic pill through the gut. Ten men and 10 women with regular daily bowel movements swallowed this pill and 10 radio-opaque markers at 8 pm. Five hours of recordings were conducted during 2 following mornings. Origin, direction, amplitude and velocity of movements were analysed relative to space-time plots of the pill trajectory. Abdominal radiographs were taken to compare the progress of both pill and markers. The magnetic pill lay idle for 90% of its sojourn in the colon; its total retrograde displacement accounted for only 20% of its overall movement. Analysis of these movements showed a bimodal distribution of velocities: around 1.5 and 50 cm min(-1), the latter being responsible for 2/3 of distance traversed. There were more movements overall and more mass movements in males. Net hourly forward progress was greater in the left than right colon, and greater in males. The position of the magnetic pill correlated well with the advancement of markers. MTS showed patterns and propulsion dynamics of colonic segments with as yet unmet precision. Detailed analysis of slow and fast patterns of colonic progress makes it possible to specify the motility of colonic segments, and any variability in gender. Such analysis opens up promising avenues in studies of motility disorders.