L'utilisation du plutonium (Pu(IV) pour des applications militaires et civiles peut engendrer des contaminations internes chez les personnes exposées. Plusieurs voies de contamination sont possibles : par ingestion, par inhalation ou par blessure. En cas d'inhalation, le plutonium se présente le plus souvent sous forme de particules d'oxyde de plutonium qui vont se localiser au sein des alvéoles pulmonaires. Par un mécanisme de phagocytose, les particules sont internalisées par les macrophages de l'épithélium pulmonaire. Actuellement, le seul agent de décorporation administré en cas de contamination au plutonium est le DTPA (l'acide diethylenetriaminepentaacetique). Il est administré en France sous forme de CaNa3-DTPA par injection intraveineuse et est efficace pour les contaminations par ingestion et par blessure. Les nanoparticules fonctionnalisées à base de polymères naturels sont un concept innovant de décorporation du Pu(IV) solubilisé dans les macrophages pulmonaires et ouvrent la voie au développement de nouvelles familles de décorporants. C'est dans ce contexte que deux stratégies ont été développées : des nanoparticules à base de N-trimethyl chitosan fonctionnalisées par le ligand DTPMP (l'acide diéthylènetriaminepentamethylene phosphonique) qui est l'analogue phosphonique du DTPA et des nanoparticules chélatantes à base de -cyclodextrines amphiphiles anioniques. Ce travail a consisté en la synthèse et la caractérisation des nano-objets puis de l'étude de leur complexation avec les actinides (Th/Pu) en utilisant la spectroscopie EXAFS. Et enfin, des tests préliminaires biologiques in vitro ont été réalisés. Les résultats obtenus, avec les nanoparticules à base de chitosan et de DTPMP montrent que les nanoparticules présentent des tailles et une stabilité compatible avec l’application visée. D’autre part, leur affinité pour les actinides (IV) (Th,Pu) est comparable à celle du chélatant de référence, le DTPA. Enfin, les tests, effectués sur deux lignées de macrophages montrent que les nanoparticules sont internalisées très rapidement et que la matrice polysaccharidique semble se dégrader, permettant le relargage du chélateur DTPMP au niveau des sites de rétention du Pu(IV). Cette thèse constitue un travail préliminaire au développement d'une nouvelle famille d’agents décorporants plus ciblés pour une contamination au plutonium par inhalation. / The use of plutonium (Pu(IV) for military and civil applications can lead to internal contamination. There are several possible routes of contamination: ingestion, inhalation or injury. In case of plutonium inhalation, the plutonium forms oxide particles that reach the pulmonary alveoli. Through a phagocytosis mechanism, the particles are internalized by the macrophages of the pulmonary epithelium and continue to exert their toxicity. Currently, the only decorporating agent administered in the event of contamination with plutonium is DTPA (diethylenetriaminepentaacetic acid). in France, it is administered as CaNa3-DTPA by intravenous injection. This standard is effective for contamination by ingestion and injury. However, it is not effective in case of contamination by inhalation. Functionalized nanoparticles based on natural polymers constitute an innovative concept for decorporating Pu(IV) solubilized in pulmonary macrophages and open the way for the development of new families of decorporants. We investigated two strategies: chitosan-based nanoparticles functionalized by the DTPMP (diethylenetriaminepentamethylene phosphonic acid) which is the phosphonic analog of DTPA and self-organized chelating β-cyclodextrin-based nanoparticles. This work was first focused on the synthesis and characterization of the nano-objects and then on the study of their complexation abilities with actinides (Th/Pu) using EXAFS spectroscopy. Finally, preliminary in vitro biological tests were carried out. Our obtained results with DTPMP and chitosan based nanoparticles showed that these aggregates exhibit size and stability compatible with the application. Furthermore, we demonstrate their affinity for the actinides(IV) (Th, Pu) is comparable to the reference DTPA. Finally, in vitro tests realized onto macrophages show that our nanoparticles are rapidly internalized through phagocytosis and that the polysaccharide matrix seems to undergo degradation which allows the DTPMP to be released and targeted right into the sequestration sites of Pu(IV). This work constitutes a first step in the development of new family of decorporating agents with a higher efficiency in case of plutonium contamination through inhalation.

Die Aspergillose ist eine Erkrankung des Respirationstraktes bei Vögeln, vor allem in Gefangenschaft gehaltenen tropischen Papageien, Greifvögeln und Pinguinen. Itraconazol ist hierbei ein häufig eingesetztes Therapeutikum und wird in der Vogelmedizin per os verabreicht (JONES und OROSZ 2000; KELLER 2011). Es zeigten sich gute Wirksamkeiten und Resistenzlagen. Bei über 90 % der Aspergillus fumigatus Isolate aus Wild- und Hausvögeln konnte eine MHK von 0,5 µg/ml eruiert werden (BEERNAERT et al. 2009). Allerdings kam es nach oraler Gabe von Itraconazol zu einem verzögerten Wirkungseintritt sowie, vor allem bei Graupapageien, zu Nebenwirkungen (KRAUTWALD-JUNGHANNS 2011b; PSCHERER 1995). Um ausreichende Wirkspiegel in Lunge und Luftsäcken zu erreichen, ist die Verabreichung einer hohen oralen Dosis notwendig. Dies führt wiederum zu hohen systemischen Konzentrationen und somit zu hohen potenziellen Nebenwirkungen (LUMEIJ et al. 1995). Ein Ziel in der Verbesserung der Therapiemöglichkeiten der Aspergillose ist es daher, einen hohen lokalen Wirkspiegel mit gleichzeitig geringen systemischen Konzentrationen zu erreichen. Ein Ansatz besteht in der inhalativen Verabreichung von z. B. Nanosuspensionen, da hier das Medikament direkt in Lunge/Luftsäcke appliziert werden kann. Ziel dieser Arbeit war die Sammlung von ersten Daten über den Einsatz einer neuartigen Itraconazol-Nanosuspension zur Verabreichung per inhalationem an Tauben (Columba livia f. domestica). Hierzu wurden in einer ersten Studie pharmakokinetische Spiegel in Blut sowie Lungengewebe nach einmaliger Gabe zweier Konzentrationsstufen (1 % und 10 %) erfasst. In der zweiten Studie wurde die Verträglichkeit sowie die Pharmakokinetik nach 14 tägiger Inhalation der Suspension in den Dosierungsstufen 1 %, 4 % und 10 % evaluiert. In der ersten Studie wurden die Tauben in zwei Hauptgruppen sowie eine Placebogruppe randomisiert aufgeteilt und erhielten einmalig über 30 min die Itraconazol-Nanosuspension per inhalationem in den Dosierungsstufen 1 % und 10 % bzw. isotonische Natriumchlorid-Lösung. Keines der Tiere zeigte Nebenwirkungen, die in Zusammenhang mit der Medikation gestellt werden konnten. Zur Erstellung eines pharmakokinetischen Profils wurden Blutproben nach 1 h, 4 h, 24 h, 48 h, 72 h und 96 h sowie Lungengewebe von je vier Tauben nach der Euthanasie entnommen und darin die Itraconazol sowie die OH Itraconazol Konzentrationen bestimmt. Alle vorhandenen Werte zu einem gegebenen Zeitpunkt wurden gemittelt, woraus sich ein zusammengesetztes Profil ergab. Nach singulärer Verabreichung zeigten sich geringe systemische Spiegel mit einer Peak-Konzentration von 0,01 µg/ml Itraconazol 4 h post inhalationem bzw. 0,04 µg/ml OH-Itraconazol 24 h post inhalationem bei der 1%igen Nanosuspension und 0,065 µg/ml Itraconazol 24 h nach der Inhalation bzw. 0,365 µg/ml OH Itraconazol 24 h nach der Inhalation bei der 10%igen Dosierungsgruppe. In den Lungen konnten weitaus höhere Spiegel mit 9,1 µg/g Itraconazol und 0,223 µg/g OH Itraconazol 1 h post inhalationem bei der 1%igen Dosierungsgruppe bzw. 91,13 µg/g Itraconazol 1 h nach der Inhalation und 1,081 µg/g OH Itraconazol 4 h nach der Inhalation bei der 10%igen Dosierungsgruppe detektiert werden. Bei der zweiten Studie wurden die Tiere in drei Hauptgruppen sowie eine Placebogruppe randomisiert aufgeteilt und erhielten 14 Tage lang über je 30 min die Itraconazol-Nanosuspension per inhalationem in den Konzentrationen 1 %, 4 % und 10 % bzw. istotonische Natriumchlorid Lösung. Zur Abklärung der Verträglichkeit wurden die Tiere täglich adspektorisch, sowie alle sieben Tage ausführlich klinisch untersucht. Weiterhin wurden vor und nach der Inhalationsperiode detaillierte Blutuntersuchungen durchgeführt. Bei keiner der Untersuchungen konnten Unverträglichkeitsreaktionen auf das zu testende Medikament festgestellt werden. Auch nach 14 tägiger Gabe konnten im Plasma nur geringe Itraconazol-/OH Itraconazol-Konzentrationen gemessen werden. Aufgrund der teilweise sehr hohen Lungenspiegel (17,14 µg/g bei der 4%igen und 185 µg/g bei der 10%igen Nanosuspension je 24 h post inhalationem) und hohen Eliminationshalbwertszeiten (von über 40 h) sind jedoch hohe und langanhaltende Wirkspiegel am Infektionsort gegeben. Abschließend kann gesagt werden, dass die erlangten Daten über den Einsatz der neuartigen Itraconazol-Nanosuspension zur Verabreichung per inhalationem bei Tauben keine klinischen Nebenwirkungen erkennen ließen und sich ein effektives pharmakokinetisches Profil zeigte. Mit den hohen lokalen Lungenspiegeln nebst geringen systemischen Konzentrationen und somit geringen zu erwartende Nebenwirkungen erscheint das Medikament durchaus zum Einsatz gegen die Aspergillose bei Vögeln geeignet zu sein.

Bei IL-10 handelt es sich um ein antiinflammatorisches Zytokin, dessen immunmodulatorische Effekte bereits in zahlreichen Studien aufgezeigt werden konnten. Ziel dieser Studie war, die Unterschiede in der systemischen Inflammation und Organdysfunktion an Mäusen zu untersuchen, die nach Induktion eines hämorrhagischen Schocks, entweder inhalativ oder systemisch, mit IL-10 behandelt wurden. Männliche C57/BL6 Mäuse (6 Tiere pro Gruppe) wurden für 1.5 Stunden blutdruckkontrolliert in einen hämorrhagischen Schock versetzt. Nach anschließender Volumensubstitution wurde ihnen inhalativ oder intraarteriell rekombiniertes Maus - IL-10 verabreicht. Nach einer Gesamtversuchsdauer von 6 - bzw. 24 Stunden erfolgte die Tötung der Tiere. Die Ergebnisse der Studie zeigen, dass die lokale und systemische Verabreichung von IL-10 das Zytokinprofil der systemischen Inflammationsantwort unterschiedlich beeinflusst. Die Lunge kann durch inhalative Gabe von IL-10 geschützt werden, ohne die systemische Inflammationsantwort zu beeinflussen.

Les nanoparticules (NP) figurent aux premiers rangs des contaminants émergents prioritaires dans le champ de surveillance des grands organismes de santé et sécurité du travail. Parmi les NP les plus utilisées, on peut citer les NP d’argent (Ag). L’exposition humaine aux NP d’Ag augmente alors inévitablement avec l’accroissement de leur production et leur utilisation généralisée ce qui suscite des préoccupations sur les risques à la santé. L'objectif du projet est de mieux documenter le devenir des NP d’Ag dans l’organisme, à partir d’études expérimentales chez l’animal exposé sous différentes conditions par inhalation, la principale voie d’exposition des travailleurs. Ces informations sont nécessaires pour le développement sécuritaire de ces nouvelles technologies. Dans un premier temps, le profil toxicocinétique des NP d’Ag inhalées a été documenté. Les rats ont été exposés « nez seulement » à des NP de 20 nm pendant 6 h à une concentration cible de 15 mg/m3. L'évolution temporelle de l'élément Ag dans les poumons, le sang, les tissus et les excrétas a été déterminée pendant 14 jours après le début de l'inhalation. La cinétique des NP d’Ag inhalées a été ensuite comparée avec la cinétique d’une forme soluble de l’élément Ag suite à l’exposition au nitrate d’argent (AgNO3) dans de mêmes conditions expérimentales pour mieux comprendre leur comportement, principalement, en raison de leur dissolution et leur capacité à libérer progressivement des ions Ag+ en milieu biologique. Ainsi, dans un dernier temps, dans le but de déterminer la meilleure métrique à utiliser pour mieux évaluer les risques associés à ces NP d’Ag, nous avons étudié l’impact de la cinétique entre un nombre plus faible et un nombre plus élevé de particules. Les profils cinétiques des NP d’Ag inhalées ont montré que la fraction de la dose inhalée qui a atteint les poumons est rapidement éliminée au cours des 72 premières heures suivant l'inhalation, puis la fraction restante de la dose est lentement éliminée par la suite. La dose inhalée éliminée des poumons semble être transférée dans la circulation systémique et atteint un maximum entre 48 et 72 h après l'inhalation. Cependant, les niveaux d'Ag dans le sang étaient faibles, ce qui suggère une biodistribution rapide dans les tissus tels que le foie, l’organe cible des NP d’Ag chez le rat après inhalation. Une translocation vers le bulbe olfactif et les ganglions lymphatiques était évidente durant l'exposition par inhalation de 6 h jusqu'à 6 h après la fin de l'exposition, démontrant l’occurrence d’un transport direct des NP d’Ag via le nerf nasal par le transport axonal et via la circulation lymphatique après la clairance pulmonaire, respectivement. Les profils d'excrétion ont également révélé que l'excrétion fécale est la voie d'excrétion dominante pour les NP d’Ag. Les résultats obtenus après l'inhalation d'AgNO3 ont montré des différences dans la cinétique de l’Ag sous la forme soluble par rapport à la forme insoluble (nanoparticulaire) avec des niveaux plus élevés dans le sang, le tractus GI et les tissus extrapulmonaires, mais des niveaux plus faibles dans les poumons. En plus de ces observations, l'évolution temporelle de l’Ag dans le tube digestif et les fèces après l'exposition à la forme soluble était associée à une réabsorption intestinale de l'Ag. Une fraction plus élevée de la dose a été également récupérée dans les reins et l'urine pour les formes solubles d’Ag; en effet, la filtration glomérulaire des agrégats de NP d’Ag peut être limitée alors que le cation monovalent dissous peut plus facilement passer dans le filtrat du sang. Notre étude a également révélé des différences significatives dans les profils temporels de l'Ag dans les poumons, le sang, les ganglions lymphatiques et le tractus gastro-intestinal entre les rats exposés à des aérosols de NP d'Ag avec un nombre faible et un nombre élevé de particules, mais dont la concentration massique est identique. Certaines similitudes entre les deux conditions ont également été notées, telles que la distribution tissulaire relative, le temps jusqu'aux niveaux de pointe (Tmax) et les profils d'excrétion. Cependant, pour confirmer si le modèle de biodistribution des NPs d'Ag est conditionné par le nombre de particules, des investigations supplémentaires sont nécessaires. / Nanoparticles (NPs) are among the top priority emerging contaminants in the monitoring field of the major occupational health and safety organizations. Among the most widely used nanoparticles, we can cite silver nanoparticles (Ag). Human exposure to Ag NPs inevitably increases with the increase in their production and their widespread use which raises concerns about the health risks. The objective of the project is to better document the fate of Ag nanoparticles in the body, based on experimental studies in animals exposed under different conditions by inhalation, the main route of exposure for workers. This information is necessary for the safe development of these new technologies. First, the toxicokinetic profile of inhaled Ag NPs was documented. Rats were exposed "nose only" to 20 nm NPs for 6 h at a target concentration of 15 mg/m3. The temporal evolution of the Ag element in the lungs, blood, tissues and excreta was determined for 14 days after the start of inhalation. Thus, to better understand their behavior, mainly because of their dissolution and their capacity to progressively release Ag+ ions in the biological medium, the kinetics of inhaled Ag NPs were compared with the kinetics of a soluble form of the element Ag following exposure to silver nitrate (AgNO3) under the same experimental conditions. Thus, as a last step, in order to determine the best metric to use to better assess the risks associated with these Ag NPs, we studied their kinetic from inhalation studies by comparing the effect of a lower -number with a higher- number of particles. The kinetic profiles of inhaled Ag nanoparticles showed that the fraction of the inhaled dose that reached the lungs is rapidly eliminated during the first 72 hours after inhalation, and the remaining fraction of the dose is slowly eliminated thereafter. The inhaled dose cleared from the lungs appears to be transferred to the systemic circulation and reaches a maximum between 48 and 72 hours after inhalation. However, Ag levels in the blood were low, suggesting rapid biodistribution to tissues such as the liver, the target organ of Ag nanoparticles in rats after inhalation. A translocation of Ag NPs in olfactory bulbs and lymph nodes was apparent, demonstrating the occurrence of direct transport of Ag NPs through nasal nerve by axonal transport and via lymphatic circulation after lung clearance, respectively. The excretion profiles also revealed that fecal excretion is the dominant excretion route for Ag nanoparticles. The results obtained after inhalation of AgNO3 showed differences in the kinetics of soluble AgNO3 compared to insoluble Ag NPs, with higher levels in blood, GI tract and extrapulmonary tissues, but lower levels in lungs. In addition to these observations, the time courses of Ag elements in the GI tract and feces following ionic form exposure were compatible with an intestinal reabsorption of Ag. A higher fraction of the dose was further recovered in kidneys and urine after AgNO3 inhalation compared to Ag NP inhalation. Indeed, filtration of Ag NP aggregates may be restricted while the dissolved Ag+ monovalent ion can more easily pass into the filtrate from blood. Our study also revealed significant differences in the time profiles of Ag element in lungs, blood, lymphatic nodes and GI tract between rats exposed to Ag NPs aerosols of lower- and higher-total particle number counts, but with the same mass concentration. Some similarities between the two conditions were also noted, such as the relative tissue distribution, time-to-peak levels (Tmax) and excretion profiles. However, to confirm if the biodistribution pattern of Ag NPs is conditioned by the particle number, further investigations are needed.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

This dissertation project aimed to demonstrate that pulmonary delivery of two anorectic gut secreted peptides, peptide YY (PYY) and oxyntomodulin (OXM) enabled food intake suppression and reduced body weight gain in rats via their systemic absorption from the lung and interaction with the brain. After PYY and OXM were administered to the lungs at varying doses, food intake and body weight gain were monitored in freely feeding rats. Significant 30-35 % food intake suppression was achieved for 4-6 h following pulmonary administration of endogenously active PYY3-36 and OXM1-37 at 0.80 and 0.50 mg/kg, respectively. Moreover, when administered daily for 7 days, these peptides enabled significant reduction of body weight gain by 39.4 and 62.3 %, respectively. However, neither of their active fragment peptides, PYY13-36, OXM30-37 and NAc-OXM30-37 was effective at doses equimolar to the effective doses of PYY3-36 and OXM1-37. For PYY3-36, its pulmonary administration caused c-Fos activation in the hypothalamus arcuate nucleus (ARC) only, which was concurrent to reduced orexigenic neuropeptide Y (NPY), suggesting its appetite suppression was mediated via the central nervous system (CNS). In contrast, OXM1-37 caused c-Fos activation in both the hypothalamus ARC and brainstem AP, which implied the involvement of the CNS control and vagal stimulation for this peptide. As it was clear that these effects resulted from their lung absorption and increased plasma levels, the pharmacokinetics of one of the peptides, PYY3-36 was characterized following pulmonary administration. The plasma profiles were dose-proportional and kinetically, non “flip-flop”, yielding the highest PYY3-36 concentrations (Cmax) of 75.0±9.3 and 726.3±69.0 ng/ml at 0.08 and 0.80 mg/kg, respectively, at 10 min. According to a new kinetic model developed in this project, the percent absolute bioavailability (% F) was estimated to be 12-14 %, as derived from the lung absorption (ka) and non-absorptive loss rate constant (knal) of 0.03 min-1 and 0.17-0.22 min-1, respectively. Overall, this research provided the first proof-of-concept for effective appetite suppression with pulmonary delivery of anorectic gut secreted peptides via systemic absorption.

<p>Dry Powder inhalers (DPIs) have been one of the most promising developments in pulmonary drug delivery systems. In general, DPIs are more effective than systemic administrations and convenient to use. However, delivering high-dose antibiotics through a DPI is still a challenge because high powder load may need a very large inhaler or increase the incidence of local adverse effects. Spray drying has been increasingly applied to produce DPI formulations for high-dose antibiotics; nevertheless, many spray-dried particles are amorphous and physically unstable during storage, particularly under the humid environment. </p> <p> </p> <p>My research focuses on addressing critical challenges in physical stability of DPIs for spray-dried high-dose antibiotics. The effects of moisture-induced crystallization on physical stability and aerosol performance of spray-dried amorphous Ciprofloxacin DPI formulations stored at different humidity conditions were studied. Our study not only provided a mechanistic understanding in the impact of crystallization on aerosol performance but also developed novel approaches for improving stability of spray-dried formulations used in DPI.</p> <p> </p> <p>Our work has shown that recrystallization of amorphous spray-dried Ciprofloxacin led to significant changes in aerosol performance of DPIs upon storage, which cause critical quality and safety concerns. These challenges have been solved through co-spray-drying Ciprofloxacin with either excipient such as leucine or synergistic antibiotic like Colistin. Co-spray-drying Ciprofloxacin with Colistin not only improved physical and aerosol stability but also enhanced antibacterial activity which is a great advantage for treating ‘difficult to cure’ respiratory infections caused by multidrug resistant bacteria.</p> <p> </p> <p>My research work is a sincere effort to maximize the utility and efficacy of high-dose DPI, an effective delivery tool for treating severe resistant bacterial respiratory infections.</p>

Introdução: surtos de asma, por poeira da soja, têm sido relatados, havendo casos fatais. Objetivo: correlacionar exposição, sensibilização e alergia respiratória a esta, no Brasil. Métodos: 590 voluntários (testes de punctura e dosagem de IgE específica). Resultados: operários da indústria apresentaram 15% de. sensibilização à soja. Caminhoneiros 22%. Moradores no entorno da indústria 22% enquanto aqueles que residem distantes 6%. .Na região agrícola distante das plantações 13% e em meio à soja 28% com 5% de sensibilizados somente à soja. O percentual de IgE positivas para soja foi 16%. Houve marcante sensibilização aos fungos. Conclusão: A prevalência de sensibilização à soja demonstra o impacto desse tipo de poluição. A sensibilização aos fungos que colonizam a soja estocada não deve ser subestimada / Background: Asthma outbreaks, by soybean dust inhalation, have been reported fatal cases.. Objective: To correlate exposure and sensitization to soybean dust in Brazil.. Methods: 590 volunteers exposed to soy dust. Prick skin tests were performed and specific IgE were measured in sera.. Results: the workers from the oil refinery had sensitization to soy (15%). Truck drivers 22%. Industry neighborhood 22%. and people who live far from this place presented only 6%. People from agricultural area far from the soy plantations 13% and in the middle of the soy 28%.with 5% sensitized only by soybean . Positive IgE was 16 %. Conclusion: a high prevalence of sensitivity to soybean hull demonstrates the impact of this kind of pollution. The sensitization to the fungi which colonize soybean storage can not be underestimated

Foram utilizados vinte ovinos, machos com idade entre um e três anos, com peso médio de 33,1 ± 3,1 kg. Os animais foram distribuídos de forma aleatória em três grupos, designados como GH (halotano), GI (isofluorano) e GS (sevofluorano) em experimento do tipo cruzado com intervalo mínimo de 1 semana entre os tratamentos. Numa primeira etapa, os animais foram anestesiados com auxílio de máscara facial, intubados e mantidos sob anestesia com agente segundo a determinação de cada grupo e obtida a concentração alveolar mínima (CAM) dos agentes por meio de estímulo nociceptivo com eletroestimulação. Em uma segunda etapa, os animais foram mantidos com a CAM previamente compreendendo os momentos de M0 a M8 com intervalo de 15 minutos entre os mesmo. Foram avaliadas as funções hemodinâmicas, respiratórias, hemogasométricas, endócrinas e o índice biespectral. Os valores médios de CAM foram de 0,71 ± 0,09%, 1,31 ± 0,33% e 2,69 ± 0,29% para o halotano, isofluorano e sevofluorano respectivamente. Houve redução dos valores do índice cardíaco no GI em todos os momentos comparativamente ao basal (p<0,001); na comparação entre os grupos os valores do M0 no GI foram superiores aos verificados em GH e GS (p<0,01). O valores do volume e índice sistólico foram inferiores ao basal a partir de M6 no grupo GH (p<0,05) e no GI todos os momentos foram inferiores ao basal (p<0,001); na comparação entre os grupos verificou-se que os valores dessas variáveis no momento M0 no GI foram superiores a GH (p<0,05) e GS (p<0,001). As médias da pressão venosa central foram inferiores no grupo GH em todos os momentos comparativamente a M0 (p<0,001), e neste mesmo momento, as médias foram superioriores comparativamente aos outros grupos (p<0,05). Quanto ao índice de resistência vascular sistêmica, os valores foram superiores nos momentos M6, M3 e M7 nos grupos GH (p<0,05), GI (p<0,001) e GS (p<0,01), respectivamente; houve incremento do índice de resistência vascular periférica no momento M7 (p<0,01) no grupo GH a partir de M3 (p<0,001), em GI e em M7 e M8 (p<0,05) comparativamente ao basal. Os valores de tensão de dióxido de carbono no final da expiração foram superiores no grupo GH a partir de M4 (p<0,05) e no GI a partir de M3 (p<0,01) comparativamente ao basal. Os valores do índice biespectral no GI, foram superiores a partir de M5 em relação ao valor basal (p<0,01); na comparação entre os grupos, os momentos M2 e M3 foram inferiores no GI comparativamente ao GH e GS (p<0,05). Houve redução da temperatura retal em todos os grupos e momentos comparativamente ao valor basal (p<0,001). O período de recuperação foi superior no grupo GH (p<0,05). Nas condições do presente estudo a CAM em ovinos é de 0,71%, 1,31% e 2,69% para o halotano, isofluorano e sevofluorano respectivamente; os três agentes promovem redução do débito cardíaco e do volume sistólico; os valores do índice biespectral são semelhantes entre os fármacos, com valores inferiores quando tratados com isofluorano; há indução de estresse neuroendócrino avaliado por meio da dosagem de cortisol; os agentes promovem hipotermia tempo dependente; o halotano promove recuperação anestésica mais prolongada. / Twenty sheep, all males, were used in this experiment. Age ranged from one to three years and mean weight was 33.1 ± 3.1 kg. In a crossover design, animals were randomly treated with halothane (GH), isoflurane (GI) and sevoflurane (GS), with interval of 1 week between treatments. In a first phase, anesthesia was induced by facemask, animals were then intubated and anesthesia maintained with one of the three treatments. Minimum alveolar concentration (MAC) was obtained by nociceptive stimulation for each animal. In phase 2, the animals were anesthetized again by facemask and maintained at the predetermined MAC (Phase 1) for two hours. Data was collected at moments (M0-M8) with intervals of 15 minutes. Cardiovascular, respiratory and bispectral index parameters were recorded. Blood gas analysis, CBC and cortisol levels were also measured and recorded. MAC of each group were 0.71± 0.09%, 1.31 ± 0.33% e 2.69 ± 0.29% for GH, GI and GS respectively. There was a reduction in cardiac index in GI at all times compared to baseline (p<0.001). Among groups the values of M0 in GI were higher than those in GH and GS (p<0.01). In GH, the end systolic volume and stroke index were lower than baseline from M6 until the end of the experiment (p<0.05). In GI, ESV and SI were below the baseline at all times (p<0.001). Among groups it was found that the GI baseline values of these variables were higher than GH (p<0.05) and GS (p<0.001). The mean central venous pressure were lower in the GH group at all times compared to M0 (p<0.001), which was higher than the baseline of the other groups (p<0.05). When compared to baseline, systemic vascular resistance index was higher in the moments M6, M3 and M7 in GH (p<0.05), GI (p<0.001) and GS (p<0.01), respectively. There was an increase in peripheral vascular resistance index (PVRI) at the time M7 (p<0.01) in GH from M3 to the end of the study (p<0.001). In GI, PVRI was increased at M7 and M8 (p<0.05) in comparison to baseline. The values of end-tidal of carbon dioxide were higher than baseline in the GH group from M4 (p<0.05) until the end of study. The same occurred in GI starting at M3 (p<0.01). In GI, the bispectral index values were higher starting at M5 to the end when compared to baseline (p<0.01). Among groups, BIS was lower at M2 and M3 in GI when compared to GH and GS (p< 0.05). Rectal temperature decreased in all groups at all moments in comparison to baseline (p<0.001). The recovery period was longer in GH (p<0.05). Under this study conditions MAC in sheep were 0.71%, 1.31% and 2.69% for halothane, isoflurane and sevoflurane, respectively. All treatments further reduced cardiac output and stroke volume; bispectral index values were similar among drugs, with lower values when treated with isoflurane. A stress response was believed to be induced due to elevation of serum cortisol in all groups. These inhalants promote time-dependent hypothermia. Halothane anesthesia promotes prolonged recovery.