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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
121

Absorption and Tissue Distribution of Drug-Like Compounds: Quantitative Structure-Activity Relationship Analysis / Vaistinių junginių absorbcija ir pasiskirstymas audiniuose: kiekybinio struktūros ir aktyvumo ryšio analizė

Lanevskij, Kiril 03 October 2011 (has links)
The objective of this work was to develop mechanistic quantitative structure activity relationship models that would facilitate the assessment of drug properties related to their absorption and distribution in the body. The analysis involved several parameters reflecting the rate of passive diffusion across brain endothelium and intestinal epithelium, and thermodynamic constants related to drug distribution between plasma and tissues. Permeation through cellular transport barriers was modeled by nonlinear equations relating the passive diffusion rate to physicochemical properties of drugs: lipophilicity, ionization, hydrogen bonding potential and molecular size. It was demonstrated that brain endothelium and intestinal epithelium exhibit a quantitatively similar pattern of permeability-ionization dependence – ionized species permeate 2-3 orders of magnitude slower than neutral molecules. Analysis of tissue to plasma partitioning data revealed the necessity to split original experimental values into separate terms reflecting plasma and tissue binding strength. Drugs’ affinity to tissues could then be described by their lipophilicity, whereas detrimental effect of ionization was only observed for acidic drugs. Finally, it was shown that a linear combination of quantitative blood-brain barrier transport parameters allows classifying drugs according to their access to central nervous system with 94% overall accuracy. / Šiame darbe pristatomi mechanistiniai kiekybinio struktūros ir aktyvumo ryšio modeliai, skirti vaistinių junginių savybių, charakterizuojančių jų absorbciją ir pasiskirstymą organizme prognozavimui. Nagrinėjama keletas parametrų, apibūdinančių paprastos difuzijos per biologines membranas greitį, taip pat termodinaminės konstantos, aprašančios vaistų pasiskirstymą tarp kraujo plazmos ir audinių. Ląstelinių pernašos barjerų pralaidumas buvo modeliuojamas netiesinėmis lygtimis, siejančiomis paprastos difuzijos greitį su vaistų fizikocheminėmis savybėmis, tokiomis kaip lipofiliškumas, jonizacija, vandenilinių ryšių sudarymo potencialas ir molekulių dydis. Nustatyta, kad smegenų endotelyje ir žarnyno epitelyje stebima panašaus pobūdžio difuzijos greičio priklausomybė nuo jonizacijos – katijonai ir anijonai difunduoja atitinkamai 2 ir 3 eilėmis lėčiau už neutralias molekules. Pademonstruota, kad analizuojant vaistų pasiskirstymo tarp audinių ir kraujo duomenis, būtina paversti pradines eksperimentines vertes kitais dydžiais, atspindinčiais vaistų jungimosi prie plazmos ir audinių komponentų stiprumą. Vaistų giminingumas audiniams gali būti aprašytas jų lipofiliškumu, o neigiama jonizacijos įtaka stebima tik rūgštiniams junginiams. Taip pat parodyta, kad vaistų pernašos per hematoencefalinę užtvarą kiekybinių parametrų tiesinė kombinacija leidžia 94% tikslumu klasifikuoti vaistus pagal jų prieinamumą centrinei nervų sistemai.
122

The role fo the adrenergic system in the recovery of motoneuron excitability and spasms after spinal cord injury

Rank, Michelle Maria Unknown Date
No description available.
123

Examining the integrity of the blood-brain barrier (BBB) and the use of lysophosphatidic acid (LPA) to modulate the barrier properties

On, Ngoc H. 03 1900 (has links)
INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.
124

Development of a Phased Array Focused Ultrasound Transducer for Two-photon Microscopy Guided Neural Studies

Shaffaf, Leila 27 November 2013 (has links)
Focused ultrasound combined with intravenously injected microbubbles is a promising non-invasive therapy capable of temporarily disrupting the blood-brain barrier for targeted drug delivery. Established in vivo experiments on rodent models combine focused ultrasound treatment with two-photon microscopy imaging to improve understanding of microvasculature response. A phased array, an advanced ultrasound therapy device, was successfully developed to improve pressure transmission in these experiments. An investigation of transducer sensitivity to setup equipment suggested modifications to setup procedures, for example recording objective position, may improve in situ pressure estimates. A ring array composed of 50 lateral mode elements, geometry determined by pressure field simulations, was successfully fabricated. Fibre optic hydrophone pressure field measurements confirmed the device had an appropriate focal size (0.7mm diameter x 4mm axial length) and reached therapeutic pressure levels (>0.5MPa). Ex vivo transcranial measurements demonstrated moderate focal correction and off-axis steering capabilities that may improve experimental throughput and target alignment.
125

Development of a Phased Array Focused Ultrasound Transducer for Two-photon Microscopy Guided Neural Studies

Shaffaf, Leila 27 November 2013 (has links)
Focused ultrasound combined with intravenously injected microbubbles is a promising non-invasive therapy capable of temporarily disrupting the blood-brain barrier for targeted drug delivery. Established in vivo experiments on rodent models combine focused ultrasound treatment with two-photon microscopy imaging to improve understanding of microvasculature response. A phased array, an advanced ultrasound therapy device, was successfully developed to improve pressure transmission in these experiments. An investigation of transducer sensitivity to setup equipment suggested modifications to setup procedures, for example recording objective position, may improve in situ pressure estimates. A ring array composed of 50 lateral mode elements, geometry determined by pressure field simulations, was successfully fabricated. Fibre optic hydrophone pressure field measurements confirmed the device had an appropriate focal size (0.7mm diameter x 4mm axial length) and reached therapeutic pressure levels (>0.5MPa). Ex vivo transcranial measurements demonstrated moderate focal correction and off-axis steering capabilities that may improve experimental throughput and target alignment.
126

A model for examining antinuclear antibody circulation and binding capabilities of human serum from systemic lupus erythematosus patients

Griffin, Marley A. January 2007 (has links)
Antinuclear antibodies (ANA) are used in screening and diagnosis of autoimmune connective tissue disorders including systemic lupus erythematosus (SLE). CNS related disorders are prevalent in SLE patients (–80%) and ANA binds specific sites within the brain. To investigate ANA infiltration across the blood-brain barrier (BBB), an ANA injectable Lewis rat model was created using 3 rat groups (saline, ANA, and ANA with histamine; since histamine promotes BBB permeability). ANA serum levels were tested for all three rat groups and rats injected with histamine demonstrated signs of histadelia. Brain slices were obtained and examined for the presence of ANA using immunofluorescence. ANA infiltration across the BBB was observed in ANA injected groups. Though the ANA and ANA histamine groups were significantly different from controls (p<0.034, p<0.030, respectively), no significance between ANA and ANA histamine groups was observed. This model could further be used to examine BBB permeability and potential drug therapy. / Department of Physiology and Health Science
127

Examining the integrity of the blood-brain barrier (BBB) and the use of lysophosphatidic acid (LPA) to modulate the barrier properties

On, Ngoc H. 03 1900 (has links)
INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites.
128

The role fo the adrenergic system in the recovery of motoneuron excitability and spasms after spinal cord injury

Rank, Michelle Maria 06 1900 (has links)
Brainstem derived noradrenaline (NA) in the spinal cord functions both to increase motoneuron excitability, by facilitating calcium-mediated persistent inward currents (Ca PICs), and to inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). Spinal cord injury (SCI) results in a reduction of NA, causing a loss of Ca PICs in motoneurons below the lesion and exaggerated EPSPs to emerge. With time motoneuron Ca PICs gradually recover and are readily triggered by the exaggerated EPSPs, resulting in the development of muscle spasms. The role of the NA in the recovery of Ca PICs and muscle spasms after chronic SCI is examined in this thesis using a rat model of spasticity incorporating both the awake rat (in vivo) and the isolated rat spinal cord (in vitro). Specific activation of the adrenergic 1 receptor with agonists facilitated Ca PIC and spasms, whereas activation of the adrenergic 2 receptor with agonists decreased the EPSPs that trigger spasms. Both receptors were endogenously activated by a ligand in vivo, though the 1 receptor additionally exhibits constitutive activity (activity in the absence of NA), predominantly in vitro. The adrenergic 2 receptor was not found to be endogenously active in vitro. Use of amphetamine in rats, which causes a forced efflux of endogenous NA, confirmed the identity of the endogenous ligand as NA and demonstrated that a residual source of NA capable of facilitating the Ca PIC and spasms persists below a chronic transection. Immunohistochemical labelling for an enzyme involved in the synthesis of NA (dopamine--hydroxylase) revealed that NA is not synthesized in the spinal cord below a chronic transection, indicating that the endogenous NA is not intrinsic to the spinal cord. Peripheral injections of NA were used to demonstrate that the residual NA instead originates in the periphery (blood) and is both passively and actively transported across a compromised blood-brain barrier (BBB) after chronic injury. The peripherally derived NA activates central adrenergic receptors to modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic SCI. This novel finding highlights the importance of understanding the adaptations of neurotransmitter systems after injury when developing effective treatment strategies for spasticity.
129

In Vivo Active Drug Uptake and Efflux at the Blood-Brain Barrier : With Focus on Drug Transport Interactions

Sadiq, Muhammad Waqas January 2012 (has links)
The blood-brain barrier (BBB) controls the movement of substances into and out of the brain. The tight junctions between endothelial cells and energy dependent transporters in the BBB influence rate and extent of drug distribution to the brain. The aim of this thesis was to study different methodological and pharmacokinetic aspects of drug transport at the BBB by characterizing possible active uptake and drug-drug interactions. Therefore, advanced tools for data acquisition and analysis were applied. The role of BBB transport in early drug development, with particular emphasis on in vitro-in vivo comparisons and species differences, was also investigated. Microdialysis in rats was used to study the BBB pharmacokinetics of oxymorphone, diphenhydramine (DPHM), oxycodone and morphine. Oxymorphone, DPHM and verapamil were all found to be actively taken up at the BBB, with brain to blood unbound drug ratios of 2, 5 and 2, respectively. The effect profile for oxycodone was successfully described using the modified M3 method for censored observations. In vitro experiments indicated a competitive interaction between DPHM and oxycodone on active uptake transport to the brain. No such interaction was observed in vivo due to much lower unbound concentrations achieved, compared with the in vitro Ki values. Active uptake of morphine at the BBB was not demonstrated even at very low concentrations as it was not possible to separate the active uptake transport process from active efflux by decreasing the morphine concentration. Mice carrying the human P-gp gene (hMDR1) were used to evaluate possible species differences in P-gp function. Differences were evident between the hMDR1 and normal mice in BBB penetration of various P-gp substrates and in the effect of blockers on P-gp function. Quantitative measurements of P-gp expression levels at the BBB and a comparison with human data are crucial for the future use of the hMDR1 model. In conclusion, this thesis reports active uptake of oxymorphone, DPHM and verapamil at the BBB. In vivo interaction of DPHM and oxycodone at the BBB was found not to be significant at therapeutic drug concentrations. Furthermore species differences were found between human and mouse P-gp function at the BBB.
130

Elektronenmikroskopische Studien zur Bluthirnschranke

Krüger, Martin 27 June 2013 (has links) (PDF)
Bei der vorliegenden Arbeit handelt es sich um experimentelle Untersuchungen zu funktionellen Aspekten der neurovaskulären Einheit im Tiermodell. Mittels Licht,- Fluoreszenz- und der Elektronenmikroskopie sowie diverser immunhistochemischer Nachweisverfahren konnten wir verschiedene Populationen der neurovaskulären Einheit näher charakterisieren. So konnten wir nachweisen, dass im Hirnparenchym eine Population CD11c-positiver, dendritischer Zellen existiert, welche im gesunden Gehirn hauptsächlich an Prädilektionsstellen für Entmarkungsherde im Rahmen der Multiplen Sklerose vorkommt. Weiterhin zeigten wir im Tiermodell, dass die über Diphterietoxin vermittelte Oligodendrozytendepletion mit einer Demyelinisierung der Axone im Gehirn einhergeht, wobei die Freisetzung und Drainage der Antigene in zervikale Lymphknoten keine gegen das Gehirn gerichtete Autoimmunität auslöst. Ebenso untersuchten wir den Beitrag endothelialer Tight junctions zur Bluthirnschrankenstörung im Modell der fokalen Ischämie an der Ratte. Hierbei waren wir in der Lage nachzuweisen, dass entgegengesetzt zur herrschenden Lehrmeinung diese nicht verantwortlich für die erhöhte Gefäßpermeabilität im Rahmen des Schlaganfalls im Tiermodell zu sein scheint. Vielmehr konnten wir mit Hilfe der Elektronenmikroskopie einen neuen Mechanismus aufzeigen. Diese Ergebnisse liefern neue Erkenntnisse bezüglich der Interaktion der verschiedenen Populationen der neurovaskulären Einheit und können somit zur Entwicklung neuer Modelle verschiedener Pathologien des Zentralnervensystems beitragen.

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