There are serious security risks with the growing use of IoT devices. Historically, manufacturers prioritized profit over security due to high demand, a perspective that has evolved but remains a challenge. With this, the security of IoT devices has been overlooked, especially regarding smart bulbs, as they tend to be bundled with other IoT devices by the research community, and consequently not receive the attentionthey require. This thesis aims to identify and analyze potential threats regarding smart bulbs, and it does so by exploring proactive strategies in order to mitigate vulnerabilities. To understand the challenges smart bulbs face, some of the current applicable legislation, cyber attacks, defense mechanisms, and vulnerabilities were analyzed. Then, a network topology and a data flow diagram of a home network with smart bulbs was developed. Consequently, layers were assigned to the smart bulb, and threat modeling was performed on a each layer using STRIDE. This procedure was then formalized with a framework that encapsulates the stages of analysing the smart bulb’s landscape through threat modeling. This work contributes to the research community’s body of knowledge by providing valuable insights detailing the smart bulb’s landscape, not only through the framework but also through the conducted threat modeling, the data flow diagrams, and the information gathered regarding the threats to smart bulb security.

В настоящее время в судостроительной промышленности является актуальным применение полособульбовых профилей из титана, используемых в качестве ребер жесткости при создании крупных металлоконструкций. В данной работе рассматривается разработка технологии прессования полособульба из титанового сплава для применения в судостроении с проведением соответствующих технологических и конструкционных расчетов. Современные методы проектирования технологических процессов обработки металлов давлением неразрывно связаны с моделированием с помощью программных пакетов для анализа деформированного состояния изготавливаемого изделия. Данный анализ в свою очередь позволяет выявить возможные ошибки в процессе, способные привести к неизбежному браку, и внести необходимые коррективы для получения изделия, обладающего необходимыми свойствами. На основе проведенных в ходе работы расчетов была спроектирована пресс-матрица, являющаяся инструментом прессовой наладки при изготовлении рассматриваемого полособульбового профиля, а также проведено моделирование технологического процесса с помощью программного обеспечения QForm. В работе также рассмотрены две методики расчета калибрующего пояска для тонкостенных профилей сложной формы и сделан вывод о выборе наиболее оптимальной на основе результатов моделирования. Конечным результатом работы является полностью спроектированный технологический процесс изготовления рассматриваемого изделия, соответствующего всем требуемым геометрическим, механическими и химическим свойствам. / At present, the application of titanium bulb flats as plate stiffeners in creating large metallic constructions remains relevant and important within the shipbuilding industry. The present work is a study of engineering a technological process of creating the required bulb flat using titanium alloy for shipbuilding use, with a number of necessary technological and constructional calculations that it entails. Modern means of technological process engineering for metal working processes are based on modeling with the assistance of various strained condition analysis software. Such analysis in turn helps to detect the potential errors within the developed process that may lead to defective product, and to make necessary corrections in order to create the product that meets the desired property requirements. In this work, a press die has been designed in order to serve as a pressing tool required to make the bulb flat of the required shape, and, based on the created die, the modeling of the technological process has been performed, with the use of QForm software package. A distinction between two different die length calculation methods is made, with one being chosen as the most optimal based on modeling results. The end result of this work is a fully engineered technological process of creating the bulb flat that meets all the geometrical, mechanical and chemical property requirements.

No description available.

Thesis (MComm (Business Management))--University of Stellenbosch, 2005. / Tulips are the second largest floral commodity that is traded globally. Currently Holland controls half of the 20 billion Dollar tulip bulb market, although immense pressure from European institutions may serve to change this phenomenon in the near future. Not only do increasing labour costs and stricter legislation on the usage of pesticides impair this industry, but the Dutch government also places huge pressure on its own producers to convert scarce agricultural land into residential areas. These conditions could therefore provide a possible market opportunity for farmers from other countries. Due too the fact that the price of tulip bulbs is based on the size of the flower and the length of the floral stem, floral farmers generally gain an extra 2-3 cm stem length via physically cutting it out of the tulip bulb. Therefore, floral farmers annually destroy their whole supply of tulip bulbs, resulting in a need to reacquire bulbs from bulb growers. Due to the fact that the lifespan of cut tulip flowers is generally not more than seven days, Dutch land rezoning ought to result in tulip bulb production being the production component which could truly be relocated in a global context. In this study, an economic analysis is therefore conducted to ascertain South Africa’s potential to produce tulip bulbs in order to supply the growing demand in the Netherlands. Information was gathered by performing a literature study of existing literature and by conducting structured interviews with numerous experts in their various fields of operation. Due to the fact that expertise in South Africa was very limited, a large number of interviews were scheduled with experts from Holland and Germany. The presence of strict non-disclosure contracts resulted in a situation where interviews had to be conducted with individuals who are two to three levels removed from any relevant tulip organisation. The study was conducted through first analysing the global market from a horticultural perspective and thereafter from an economic-logistical stance. It was established that tulip bulbs are very temperature sensitive and therefore have to be produced far from any tropical zones. Since Sutherland’s winter temperature is similar to that of Dutch production areas, South African tulip bulbs could be planted in Holland. The difference in seasons of production allows farmers from the Southern Hemisphere to predict the extremely fashion sensitive market in one year less. Via moving production activities between alternative hemispheres, off seasons can be utilized for production, which could result in fashions being predicted with a greater sense of accuracy. If unfashionable bulbs are produced, a loss of up to R 34 129,87 per ha can be incurred, while mid-priced bulbs and fashionable bulbs can earn respectively R80 118,09 and R 122 626,57 per ha. Projections are however based on the prices of a bear phase where the market currently pays up to 75% less for bulbs than it did three years ago. The production costs in Sutherland could be cut by R 15 750 if it is decided to mechanise production but simultaneously this action will result in an increase of R120 000 in new capital equipment required. The use of 40 feet High Cube Reefers reduces transportation costs considerably and 1 042 437 bulbs with a circumference of between 10 and 12 cm can be shipped in such an container via utilizing South African produced SN 64190 crates and four way export pallets. Market penetration remains an important consideration since a farmer’s production history is very important in the international market environment. Partnerships, production of larger bulbs, organic production and seasonal production in alternating hemispheres, remain some of the most suitable techniques for market penetration.

Les figures de neuroanatomie de ce mémoire peuvent être téléchargées en haute résolution. / Une voie neuronale sous-tendant la locomotion induite par la détection d’odorants a été découverte chez la lamproie (Derjean et al., 2010). Le signal olfactif est relayé du bulbe olfactif médian au tubercule postérieur, puis à la région locomotrice mésencéphalique et enfin aux cellules réticulospinales qui activent les réseaux locomoteurs spinaux. Des études récentes démontrent que le bulbe olfactif médian est sous l’influence d’une inhibition GABAergique tonique qui régule les réponses des cellules réticulospinales à la stimulation du nerf olfactif (Daghfous et al., 2013). Des mécanismes de modulation supplémentaires pourraient exister dans le bulbe olfactif de Petromyzon marinus puisqu’il contient aussi des fibres dopaminergiques. Chez tous les vertébrés étudiés, la dopamine joue un rôle important dans le traitement olfactif. Des techniques anatomiques (traçage et immunofluorescence) et physiologiques (enregistrements intracellulaires) ont été utilisées pour étudier la modulation dopaminergique de la voie olfacto-motrice. L’immunofluorescence ciblant la dopamine a révélé des fibres plus nombreuses dans la partie médiane du BO et à proximité de neurones de projection et de fibres olfactives. De plus, aucun corps cellulaire immunopositif n’a été détecté dans le bulbe olfactif. L’enregistrement des réponses synaptiques des cellules réticulospinales à la stimulation du nerf olfactif a été réalisé dans le cerveau isolé in vitro. L’injection locale de dopamine dans le bulbe olfactif médian diminue de moitié l’amplitude de réponse. Sous l’effet d’un antagoniste des récepteurs GABAA dans le bain ou localement dans le bulbe olfactif médian, les dépolarisations soutenues enregistrées sont supprimées par l’injection de dopamine. Cependant, l’injection individuelle ou combinée dans le bulbe olfactif médian d’antagonistes sélectifs des récepteurs D1 ou D2, soit le SCH 23390 et l’éticlopride, demeure sans effet significatif sur les réponses olfacto-motrices, indiquant l’absence d’activité dopaminergique tonique. Pour localiser les neurones responsables de cette modulation, des injections de traceur axonal ont été combinées avec l’immunofluorescence ciblant la dopamine. Des cellules dopaminergiques projetant au BO médian ont été observées dans les noyaux dopaminergiques du tubercule postérieur et de l’hypothalamus périventriculaire. Dans l’ensemble, nos résultats montrent anatomiquement et physiologiquement la présence d’une innervation dopaminergique dans le bulbe olfactif médian qui a une action inhibitrice sur le traitement olfacto-moteur. / A neural substrate underlying odor-evoked locomotion was revealed in lampreys (Derjean et al., 2010), involving a neural pathway extending from the medial part of the olfactory bulb to the posterior tuberculum. The signal is then relayed to the mesencephalic locomotor region and eventually reaches reticulospinal cells that activate the spinal locomotor networks. Recent research in the lab (Daghfous et al., 2013) shows that the medial olfactory bulb, is under a tonic GABAergic inhibition gating reticulospinal cell responses to olfactory nerve stimulation. Additional modulatory mechanisms might exist in the olfactory bulb of Petromyzon marinus as it also contains dopaminergic fibers. In every vertebrate studied to date, dopamine plays an important role in olfactory processing. Anatomical (axonal tracers and immunofluorescence) and physiological (intracellular recordings) techniques were used to investigate the dopaminergic modulation of the olfacto-motor pathway. Dopamine immunofluorescence showed scarce innervation of the olfactory bulb that was most abundant in the medial part and in close vicinity to projection neurons and olfactory nerve fibers. Additionally, no dopamine-immunoreactive cell bodies were detected in the olfactory bulb. Synaptic responses of reticulospinal cells to olfactory nerve stimulation were recorded in the isolated brain. Local injection of dopamine in the medial olfactory bulb induces an almost two-fold decrease of the synaptic responses. When GABAA receptor antagonist GABAzine was also injected in the medial olfactory bulb, the effect of dopamine was much more evident and could suppress large bursts of action potentials. However, D1 (SCH 23390) and D2 (Eticlopride) receptor antagonists injection in the medial olfactory bulb failed to alter the amplitude of reticulospinal cell responses to olfactory nerve stimulation, indicating that this modulation is not tonic. To locate the neurons responsible for this modulation, tracer injections combined with dopamine immunofluorescence were performed. Dopaminergic cells projecting to the medial olfactory bulb were found in the dopaminergic nuclei of the posterior tuberculum and the periventricular hypothalamus. Altogether, our results show anatomically and physiologically the presence of a dopaminergic innervation within the medial olfactory bulb that mediates inhibitory effects on olfacto-motor signaling.

Les conséquences liées à la présence de gradients thermiques sur le transfert de matière en milieu poreux sont encore aujourd’hui mal appréhendées, essentiellement en raison de la complexité induite par la présence de phénomènes couplés (thermodiffusion ou effet Soret). Le but de cette thèse est d’étudier et de comprendre l’influence que peut avoir un gradient thermique sur l’écoulement d’un mélange. L’objectif principal est de déterminer les coefficients effectifs modélisant les transferts de chaleur et de matière en milieux poreux, et en particulier le coefficient de thermodiffusion effectif. En utilisant la technique de changement d’échelle par prise de moyenne volumique nous avons développé un modèle macroscopique de dispersion incluant la thermodiffusion. Nous avons étudié en particulier l'influence du nombre de Péclet et de la conductivité thermique sur la thermodiffusion. Les résultats ont montré que pour de faibles nombres de Péclet, le nombre de Soret effectif en milieu poreux est le même que dans un milieu libre, et ne dépend pas du ratio de la conductivité thermique (solide/liquide). À l'inverse, en régime convectif, le nombre de Soret effectif diminue. Dans ce cas, un changement du ratio de conductivité changera le coefficient de thermodiffusion effectif. Les résultats théoriques ont montré également que, lors de la diffusion pure, même si la conductivité thermique effective dépend de la connectivité de la phase solide, le coefficient effectif de thermodiffusion est toujours constant et indépendant de la connectivité de la phase solide. Le modèle macroscopique obtenu par cette méthode est validé par comparaison avec des simulations numériques directes à l'échelle des pores. Un bon accord est observé entre les prédictions théoriques provenant de l'étude à l’échelle macroscopique et des simulations numériques au niveau de l’échelle de pores. Ceci démontre la validité du modèle théorique proposé. Pour vérifier et consolider ces résultats, un dispositif expérimental a été réalisé pour mesurer les coefficients de transfert en milieu libre et en milieu poreux. Dans cette partie, les nouveaux résultats expérimentaux sont obtenus avec un système du type « Two-Bulb apparatus ». La diffusion et la thermodiffusion des systèmes binaire hélium-azote et hélium-dioxide de carbone, à travers des échantillons cylindriques remplis de billes de différents diamètres et propriétés thermiques, sont mesurées à la pression atmosphérique. La porosité de chaque milieu a été déterminée par la construction d'une image 3D de l'échantillon par tomographie. Les concentrations sont déterminées par l'analyse en continu de la composition du mélange de gaz dans les ampoules à l’aide d’un catharomètre. La détermination des coefficients de diffusion et de thermodiffusion est réalisée par confrontation des relevés temporels des concentrations avec une solution analytique modélisant le transfert de matière entre deux ampoules. Les résultats sont en accord avec les résultats théoriques. Cela permet de conforter l’influence de la porosité des milieux poreux sur les mécanismes de diffusion et de thermodiffusion. / A multicomponent system, under nonisothermal condition, shows mass transfer with cross effects described by the thermodynamics of irreversible processes. The flow dynamics and convective patterns in mixtures are more complex than those of one-component fluids due to interplay between advection and mixing, solute diffusion, and thermal diffusion (or Soret effect). This can modify species concentrations of fluids crossing through a porous medium and leads to local accumulations. There are many important processes in nature and industry where thermal diffusion plays a crucial role. Thermal diffusion has various technical applications, such as isotope separation in liquid and gaseous mixtures, identification and separation of crude oil components, coating of metallic parts, etc. In porous media, the direct resolution of the convection-diffusion equations are practically impossible due to the complexity of the geometry; therefore the equations describing average concentrations, temperatures and velocities must be developed. They might be obtained using an up-scaling method, in which the complicated local situation (transport of energy by convection and diffusion at pore scale) is described at the macroscopic scale. At this level, heat and mass transfers can be characterized by effective tensors. The aim of this thesis is to study and understand the influence that can have a temperature gradient on the flow of a mixture. The main objective is to determine the effective coefficients modelling the heat and mass transfer in porous media, in particular the effective coefficient of thermodiffusion. To achieve this objective, we have used the volume averaging method to obtain the modelling equations that describes diffusion and thermodiffusion processes in a homogeneous porous medium. These results allow characterising the modifications induced by the thermodiffusion on mass transfer and the influence of the porous matrix properties on the thermodiffusion process. The obtained results show that the values of these coefficients in porous media are completely different from the one of the fluid mixture, and should be measured in realistic conditions, or evaluated with the theoretical technique developed in this study. Particularly, for low Péclet number (diffusive regime) the ratios of effective diffusion and thermodiffusion to their molecular coefficients are almost constant and equal to the inverse of the tortuosity coefficient of the porous matrix, while the effective thermal conductivity is varying by changing the solid conductivity. In the opposite, for high Péclet numbers (convective regime), the above mentioned ratios increase following a power law trend, and the effective thermodiffusion coefficient decreases. In this case, changing the solid thermal conductivity also changes the value of the effective thermodiffusion and thermal conductivity coefficients. Theoretical results showed also that, for pure diffusion, even if the effective thermal conductivity depends on the particle-particle contact, the effective thermal diffusion coefficient is always constant and independent of the connectivity of the solid phase. In order to validate the theory developed by the up-scaling technique, we have compared the results obtained from the homogenised model with a direct numerical simulation at the microscopic scale. These two problems have been solved using COMSOL Multiphysics, a commercial finite elements code. The results of comparison for different parameters show an excellent agreement between theoretical and numerical models. In all cases, the structure of the porous medium and the dynamics of the fluid have to be taken into account for the characterization of the mass transfer due to thermodiffusion. This is of great importance in the concentration evaluation in the porous medium, like in oil reservoirs, problems of pollution storages and soil pollution transport. Then to consolidate these theoretical results, new experimental results have been obtained with a two-bulb apparatus are presented. The diffusion and thermal diffusion of a helium-nitrogen and helium-carbon dioxide systems through cylindrical samples filled with spheres of different diameters and thermal properties have been measured at the atmospheric pressure. The porosity of each medium has been determined by construction of a 3D image of the sample made with an X-ray tomograph device. Concentrations are determined by a continuous analysing the gas mixture composition in the bulbs with a katharometer device. A transient-state method for coupled evaluation of thermal diffusion and Fick coefficients in two bulbs system has been proposed. The determination of diffusion and thermal diffusion coefficients is done by comparing the temporal experimental results with an analytical solution modelling the mass transfer between two bulbs. The results are in good agreement with theoretical results and emphasize the porosity of the medium influence on both diffusion and thermal diffusion process. The results also showed that the effective thermal diffusion coefficients are independent from thermal conductivity ratio and particle-particle touching.

L’olfaction est importante pour de nombreuses fonctions vitales comme la reproduction, les interactions sociales, la détection des aliments et le comportement alimentaire. Toutefois, l'impact nutritionnel sur le système olfactif n'a pas été précisément décrit. Dans ce contexte, le sujet de cette thèse consistait en l’étude des effets du jeûne sur la représentation spatiotemporelle des odeurs dans le bulbe olfactif principal (BO), une structure assurant la première étape du codage de l'information olfactive dans le cerveau.Dans le BO, les caractéristiques des molécules odorantes sont représentées sous forme d’activitéspatiale et temporelle respectivement dans la couche glomérulaire et celles des cellules mitrales et granulaires. Pour étudier le codage spatial au niveau glomérulaire, nous avons utilisé l’imagerie optique du signal intrinsèque qui permet de cartographier l’activité évoquée sur la surface du BO en réponse à des odeurs. Pour étudier le codage temporel des odeurs, nous avons enregistré les variations spécifiques de l'activité oscillatoire du potentiel de champ local (LFP) dans les couches profondes.Nous avons testé les réponses aux odeurs chez des rats mis à jeun pendant 17 heures par rapport aux rats nourris ad libitum. Nous avons utilisé deux stimuli olfactifs à des concentrations différentes: la première (odeur commerciale d’arôme d'amande) est associée à la nourriture car elle est préalablement incorporée dans une pâte sucrée présentée aux rats quotidiennement ; le second (hexanal), est une molécule odorante pure, nouvelle et neutre pour eux. L'utilisation de ces odeurs dans une gamme de concentrations faibles nous a permis d’étudier les modifications de seuil d’activation du BO. Nous avons analysé les deux types de représentation spatiale et temporelle chez des rats anesthésiés, à jeun versus nourris. Nous avons observé que les cartes spatiales et les changements des profils oscillatoires évoqués dans le BO sont présents pour les deux types de stimuli à de faibles concentrations chez tous les rats à jeun mais pas chez tous les animaux nourris. Par contre, pour les fortes concentrations d'odeurs, nous avons observé plus de réponses chez les animaux nourris. Nous avons conclu que le jeûne affecte profondément le seuil d’activation spatiotemporelle du BO.Nous avons alors cherché à identifier les candidats moléculaires qui pourraient déclencher cetteplasticité olfactive à jeun. Nous avons analysé dans le BO la variation de l'expression des récepteurs à deux hormones satiétogènes, la leptine et l'insuline, mais n'avons pas trouvé de changement significatif entre les deux groupes de rats. En outre, l'injection intrapéritonéale de leptine n'a pas inversé le profil oscillatoire induit chez des rats à jeun. Nous avons conclu que la leptine n'agit pas à elle seule dans la signalisation de l'état nutritionnel qui induit la plasticité bulbaire. Nous avons également cherché des modifications spécifiques des circuits du BO pendant le jeûne et avons obtenu des données préliminaires intéressantes sur la plasticité astrocytaire. Enfin, nous avons mené un nouveau projet sur le rôle des endocannabinoïdes dans la prise alimentaire. Le THC est un agoniste des récepteurs CB1 aux endocannabinoïdes qui induit une hyperphagie. Les CB1 étant présents dans le BO, nous avons testé ses effets sur l'activité oscillatoire chez des souris à jeun. Nous avons trouvé que le THC inhibe la désensibilisation olfactive qui est déclenchée chez les souris contrôle par la présentation d'odeurs répétées. / Olfactory cues are important for many vital functions as reproduction, social interactions, fooddetection and feeding behavior. However, the nutritional impact on the olfactory system has not been precisely described. Here we studied the effects of fasting on the spatiotemporal activities in the main olfactory bulb (OB), a structure supporting the first step of odor coding in the brain.Odorant signals undergo a complex processing that starts in the Main Olfactory Epithelium where the olfactory sensitive neurons (OSN) are located. OSN project into the OB where odorant features (among them identity and concentration) evoke spatiotemporal patterns of activities located respectively at the glomerular and mitral/granule cells levels. The spatial coding at the glomerular level is classically studied by optical imaging of odor-evoked activities on the surface of the MOB in response to different odors at different concentrations. The temporal coding is characterized by specific variations in the oscillatory activity of the Local Field Potential (LFP) in deeper layers.We tested odor responses in the OB in 17 hours-fasted rats compared to ad libitum-fed rats. We used two olfactory stimuli at different concentrations: the first one (almond aroma odor) is associated to food since it is incorporated into a homemade cake that rats love to eat; the second is the pure odorant hexanal which is new and neutral for them. Using these odorants at low concentrations to probe threshold modifications, we analyzed both types of OB coding (spatial and temporal) at the levels where they occur (glomerular layer and mitral/granule cell layers respectively) in anesthetized rats.Using intrinsic optical signals imaging and local field potential recording, we observed that odor maps and changes in oscillatory patterns of activity in the OB are present for both types of stimuli at low concentrations in all fasted rats but not in all fed animals. For higher odor concentrations, further fed animals responded. We conclude that fasting deeply impacts the overall odor threshold detection in the OB.Then, we sought to identify putative molecular candidates that could trigger this olfactory plasticity in fasted conditions. We have checked the variation of receptor expression for leptin and insulin, two anorexigen hormones, in the OB but did not find any significant changes between the two groups. In addition, i.p. injection of leptin did not reverse the oscillatory profile induced in fasted rats. We concluded that leptin does not act solely in signalling the nutritional state that induces the OB plasticity. We are still looking for specific modifications of OB circuits during fasting and we present interesting preliminary data about astrocytic plasticity in this manuscript. Finally, we have also run a new and exciting project dealing with the role of endocannabinoids in food intake: since THC, a potent agonist of endocannabinoids CB1 receptors which are expressed in the OB, selectively increases food intake when injected at low doses, we tested its effects on the OB oscillatory activity in fasted mice. We found that THC inhibits olfactory desensitization that is triggered in control mice by repeated odor presentation.

<p>The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer.</p><p>In a mouse model, [³H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied <i>in vitro</i>. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component.</p><p>Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity.</p><p>In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new <i>in vitro</i> models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.</p>

The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer. In a mouse model, [3H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied in vitro. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component. Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity. In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new in vitro models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa. In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography. In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo. In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.